The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) The Diels±Alder Reaction The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) The Diels±Alder Reaction Selected Practical Methods Francesco Fringuelli UniversitaÁ degli Studi di Perugia, Italy Aldo Taticchi UniversitaÁ degli Studi di Perugia, Italy The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) Copyright # 2002 John Wiley & Sons, Ltd Baffins Lane, Chichester, West Sussex, PO19 1UD, England National 01243 779777 International (44) 1243 779777 e-mail (for orders and customer service enquiries): [email protected] Visit our Home Page on http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. 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The Diels Alder reaction: selected practical methods / Francesco Fringuelli, Aldo Taticchi. p. cm. Includes bibliographical references and index. ISBN 0-471-80343-X (acid-free paper) 1. Diels-Alder reaction. I. Taticchi, Aldo. II. Title. QD281.R5 F75 2002 5470 .2Ðdc21 2001024910 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0-471-80343-X Typeset in 10/12pt Times by Kolam Information Services Pvt. Ltd, Pondicherry, India. Printed and bound in Great Britain by Biddles Ltd, Guildford, Surrey. This book is printed on acid-free paper responsibly manufactured from sustainable forestry, in which at least two trees are planted for each one used for paper production. to our wives The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) Contents Preface Abbreviations and Acronyms 1 2 Diels±Alder Reaction: General Remarks 1.1 Introduction 1.2 Diene and Dienophile 1.3 Pericyclic Diels±Alder Reaction 1.4 Ionic and Radical Diels±Alder Reactions 1.5 Regiochemistry 1.6 Stereochemistry 1.7 Retro Diels±Alder Reaction 1.8 Homo-Diels±Alder Reaction 1.9 Multiple Diels±Alder Reaction 1.10 Theory 1.10.1 Reactivity and Substituent Effects 1.10.2 Regioselectivity 1.10.3 Stereoselectivity References Thermal Diels±Alder Reaction 2.1 Introduction 2.2 Carbon Diels±Alder Reactions 2.2.1 Open-Chain Dienes 2.2.2 Cyclopentadienes and Cyclohexadienes 2.2.3 Heterocyclic Dienes 2.2.4 Outer-Ring Dienes 2.2.5 Inner-Outer-Ring Dienes 2.2.6 Across-Ring Dienes 2.3 Hetero-Diels±Alder Reactions 2.3.1 Heterodienes 2.3.2 Heterodienophiles 2.4 Intramolecular Diels±Alder Reaction 2.5 Outlined Diels±Alder Reactions References xi xiii 1 1 3 4 5 10 12 15 18 20 22 22 23 24 25 29 29 29 29 37 40 43 49 64 66 66 70 74 83 92 viii 3 4 Contents Lewis-Acid Catalyzed Diels±Alder Reaction 3.1 Introduction 3.2 Carbon Diels±Alder Reaction 3.2.1 Cycloadditions of Cycloalkenones 3.2.2 Heterocyclic Dienophiles 3.2.3 Rare Earth Metals and Scandium Triflates 3.2.4 Bulky Lewis Acids 3.2.5 Heterocyclic Dienes 3.2.6 Sulfinyl Group Containing Dienes and Dienophiles 3.2.7 Transition Metal-Based Catalysts 3.2.8 Heterogeneous Catalysis 3.2.9 Chiral Catalysts 3.3 Hetero-Diels±Alder Reaction 3.3.1 Normal Diels±Alder Reactions. Synthesis of Pyrones and Thiopyrans 3.3.2 Inverse Diels±Alder Reactions. Synthesis of Pyranes 3.3.3 Pyrones and Triazines as Dienes 3.4 Homo-Diels±Alder Reaction 3.5 Cationic Diels±Alder Reaction 3.6 Outlined Diels±Alder Reactions References Diels±Alder Reaction Facilitated by Special Physical and Chemical Methods 4.1 Solid-Phase Diels±Alder Reaction 4.1.1 Inorganic Solid-Surface Promoted Diels±Alder Reaction 4.1.2 Diels±Alder Reaction Using Resin-Anchored Reagents 4.2 Ultrasound-Assisted Diels±Alder Reaction 4.3 Microwave-Assisted Diels±Alder Reaction 4.4 Photo-Induced Diels±Alder Reaction 4.5 Diels±Alder Reaction in Molecular Cavities 4.6 Micelle-Promoted Diels±Alder Reaction 4.6.1 Diels±Alder Reactions of Surfactant Reagents 4.6.2 Micellar Catalysis 4.7 Biocatalyst-Promoted Diels±Alder Reaction 4.7.1 Proteins and Enzymes Catalysis 4.7.2 Antibody Catalysis 4.8 Brùnsted Acid-Catalyzed Diels±Alder Reaction 4.9 Miscellaneous Diels±Alder Reactions 4.10 Outlined Diels±Alder Reactions References 99 99 100 100 106 108 110 110 112 114 115 116 122 122 123 126 126 128 130 138 143 143 143 149 154 158 163 170 174 174 176 180 180 183 185 190 194 200 Contents ix 5 High Pressure Diels±Alder Reaction 5.1 Introduction 5.2 Open-Chain Dienes 5.2.1 Cycloadditions with Carbodienophiles 5.2.2 Cycloadditions with Heterodienophiles 5.3 Outer-Ring Dienes 5.4 Inner-Outer-Ring Dienes 5.5 Inner-Ring Dienes 5.5.1 Cyclopentadienes and Cyclohexadienes 5.5.2 Tropones as Dienes 5.5.3 Furans and Thiophenes 5.5.4 Pyrones and Pyridones 5.6 Outlined Diels±Alder Reactions References 205 205 208 208 213 217 219 223 223 226 229 234 237 246 6 Diels±Alder Reaction in Unconventional Reaction Media 6.1 Diels±Alder Reaction in Aqueous Medium 6.1.1 Uncatalyzed Diels±Alder Reaction 6.1.2 Catalyzed Diels±Alder Reaction 6.2 Diels±Alder Reaction in Non-Aqueous Polar Systems 6.2.1 Lithium Perchlorate±Diethyl Ether 6.2.2 Lithium Perchlorate±Nitromethane 6.2.3 Lithium Trifluoromethanesulfonimide in Acetone or Diethyl Ether 6.2.4 para-Chlorophenol and Ethylene Glycol 6.2.5 Ionic Liquids 6.3 Diels±Alder Reaction in Microemulsion 6.4 Diels±Alder Reaction in Supercritical Fluids 6.4.1 Diels±Alder Reaction in Supercritical Water 6.4.2 Diels±Alder Reaction in Supercritical Carbon Dioxide 6.5 Outlined Diels±Alder Reactions References 251 251 252 261 268 268 273 274 276 278 280 284 285 286 289 297 Diels±Alder Reaction Compilation 7.1 Compilation 7.2 Keyword Index (Chapter 7) 301 301 325 7 Subject Index 331 The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) Preface The Diels-Alder reaction, probably the most widely used methodology in organic synthesis today, has contributed greatly to the development of mechanistic and theoretical chemistry. The recent discovery of a Diels±Alderase enzyme has provided insights into the mechanism of biosynthetic cycloaddition. As a follow-up to our book Dienes in the Diels±Alder Reaction (1990) and in light of our personal experience as well as the reviews and books that have been published on this topic to date, we decided that a book collecting and describing the experimental methods that have been developed to perform the Diels±Alder reaction would be a useful tool for researchers working in organic synthesis. The first chapter presents the general aspects of the reaction; Chapters 2±6 illustrate the various methods and their applications in organic synthesis. At the end of each chapter a list of graphically abstracted Diels±Alder reactions is presented to show selected synthetic applications of the specific methodology. The discussion of the various topics is not exhaustive because our aim has been to emphasize the synthetic potential of each method. Chapter 7 reports a list of books, reviews, monographs and symposia proceedings which have appeared since 1990 and an index of keywords to help the reader find a particular paper of interest. The book is directed toward undergraduate and graduate level students, as well as to academic and industrial researchers working in organic synthesis. We are grateful to Drs Assunta Marrocchi, Oriana Piermatti and Luigi Vaccaro for their assistance with the drawings. Francesco Fringuelli Aldo Taticchi The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) Abbreviations and Acronyms Ac acac AIBN Ar 9-BBN BINOL BLA BMIM Bn BOM BP Bu i-Bu t-Bu Bz CAB CAN Cat Cat* CBZ or Cbz COD Cp CSA CTAB Cy DBU DCM DDQ de DIEA DIPHOS DMAD DMF DMI DPP acetyl acetylacetonate 2,20 -azobisisobutyronitrile aryl 9-borabicyclo-[3.3.1]-nonyl 1,10 -bi-2-naphthol Brùnsted Lewis acid 1-butyl-3-methylimidazolium cation benzyl benzyloxymethyl N-1-butylpyridinium cation n-butyl iso-butyl tert-butyl benzoyl chiral acyloxyborane ceric ammonium nitrate catalyst chiral catalyst benzyloxycarbonyl or carbobenzyloxy cyclooctadiene cyclopentadienyl camphorsulfonic acid cetyltrimethylammonium bromide cyclohexyl 1,8-diazabicyclo-[5.4.0]-undec-7-ene dichloromethane 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diastereoisomeric excess diisopropylethylamine bis-(1,2-diphenylphosphino)-ethane dimethyl acetylenedicarboxylate dimethyl formamide 1,2-dimethylimidazole 2,6-diphenylpyridine xiv dppe dppp DS DTBMP DTBP E EDDA ee EG EGA EMIM FMO Fu HMPA HOMO HP HSVM HTBA IP IPB LASC LDA Ln LP-DE LP-NM LT-AC LT-DE LUMO MABR MAD Men MeOSMT MO MOM MPM or PMB MS MW NBS Abbreviations and Acronyms 2-(diphenylphosphino)ethyl 1,3-bis(diphenylphosphino) propane dodecyl sulfate 2,6-di-t-butyl-4-methylpyridine 2,6-di-t-butylpyridine CO2 Me if not otherwise specified ethylene diammonium diacetate enantiomeric excess ethylene glycol electrogenerated acid 1-ethyl-3-methylimidazolium cation frontier molecular orbital furyl hexamethylphosphoramide highest occupied molecular orbital high pressure high-speed vibration milling hexadecyltrimethylammonium bromide incident power isopropylbenzene Lewis-acid surfactant combined catalyst lithium diisopropylamide lanthanides lithium perchlorate-diethyl ether lithium perchlorate-nitromethane lithiumtrifluoromethanesulfonamideacetone lithiumtrifluoromethanesulfonamidediethylether lowest occupied molecular orbital methylaluminum-bis-(4-bromo-2,6-ditert-butylphenoxide) methylaluminum-bis-(4-methyl-2,6-ditert- butylphenoxide) menthyl methoxytrimethylsilane molecular orbital methoxymethyl p-methoxybenzyl or p-methoxyphenylmethyl molecular sieves microwave N-bromosuccinimide Abbreviations and Acronyms NMI NPM PCP Ph PMB or MPM Pr i-Pr PS-DES Py Rfx rt SBT or TBS or SMDBT or TBDMS SCF SDS SMDBT or TBDMS or SBT or TBS SMT or TMS SPDBT or TBDPS SPT or TPS TADDOL TBAF TBDMS or SMDBT or TBS or SBT TBDPS or SPDBT TBME TBPA TBS or SBT or TBDMS or SMDBT TCNE TES Tf TFA TFE TFMSA or TfOH TfOH or TFMSA Th THF Thx TMOF TMS or SMT TMSOTf Tol TPS or SPT xv 1-methylimidazole N-phenylmaleimide p-chlorophenol phenyl p-methoxybenzyl or p-methoxyphenylmethyl n-propyl iso-propyl polystyrene diethylsilane pyridil reflux room temperature t-butyldimethylsilyl supercritical fluid sodium dodecyl sulfate t-butyldimethylsilyl trimethylsilyl t-butyldiphenylsilyl triphenylsilyl a, a, a0 , a0 -tetraaryl-1,3-dioxolane-2dimethyl-4,5-dimethanol tetra-n-butylammonium fluoride t-butyldimethylsilyl t-butyldiphenylsilyl t-butyl methyl ether tris(bromophenyl)ammoniumhexachloroantimoniate t-butyldimethylsilyl tetracyanoethylene triethylsilyl trifluoromethanesulfonyl (trifyl) trifluoroacetic acid 1,1,1-trifluoroethanol trifluoromethanesulfonic acid trifluoromethanesulfonic acid thienyl tetrahydrofuran 2,3-dimethyl-2-butyl (thexyl) trimethyl orthoformate trimethylsilyl trimethylsilyl trifluoromethane sulfonate tolyl triphenylsilyl xvi Ts TTA TTMSS US D Abbreviations and Acronyms tosyl or p-toluensulfonyl tris-(p-tolyl)aminium tris-trimethylsilylsilane ultrasonic, ultrasonication heating The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) Index This index does not include Chapter 7. Page references followed by `t' refers to tables. L-abrine 266 acetals 70, 71, 187, 189, 192 (E)-1-acetoxybutadiene 208 4-acetoxy-2-cyclopenten-1-one 104, 105, 220, 221, 223 acetoxymaleic anhydride 38 2-acetoxypyran-2-one 235 acetyl chloride 165 acetylene see ethyne acrolein 24, 115, 144, 266 acrylates 145, 266, 267, 278 acrylonitrile 44, 170, 228, 252, 279 3-acryloyl-1,3-oxazolidin-2-one 116 N-acryloyl oxazolidones 133, 190 (R)-O-acryloylpantolactone 146 1-acylnaphthalenes 197 acyl-1,3-oxazolidin-2-ones 118 2-acyloxyacroleins 86 aklavinone 207 Alder's rule 14 aldol condensation 268 alkaloids 9, 60, 62 cinchona 190, 191t pyrrolophenanthridine 272, 294 alkenes, exocyclic 90 alkylcyclohexenones 5 5-alkylidene-1,3-dioxane-4,6-dione 166, 196 N-alkyl maleimides 253, 254t alkynes 32 N-allylic enamides 191, 200 alumina 115, 133, 143, 146, 147, 161, 162, 194, 195 aluminum trichloride 5, 23, 99, 104 aluminum trisphenoxide 138 a-amino acids 107 o-aminobenzylalcohols 67 tert-aminodienylesters 88 2-aminofurans 272 2-aminomethylbutadienes 32 anthracene 99, 157, 168, 193, 287 maleic anhydride and 160, 163 anthracene-9-carbinol 252, 253, 254t 1-(2H)-anthracenone 219 anthrone 7, 8 arylethenes 219, 223 arynes 70, 87 see also benzyne arysugacin 88 asymmetric Diels±Alder reactions 83, 112, 117, 132, 240, 244, 266 catalyzed 137, 145, 146, 186t, 296 enantioselection 117 heterocyles and 73 tetrahydrocarbazoles and 64 aza-Diels±Alder reactions 132, 137, 187, 262, 271, 290, 293 azacyclophane CP66 173 azadienes 66, 67, 154, 264 azadirachtin 75 azanaphthoquinones 155 azulene quinones 229, 238 benzaldehyde 6, 167, 185 benzanilides 211 1-benzenesulfonyl-2trimethylsilylacetylene 37 benzo[c]furans (isobenzofurans) 41 1,4-benzodioxanes 83 1,4-benzoquinone 34, 56, 80, 144, 206 2-vinylthiophene and 58 anthracene and 99, 157 1,3-butadiene and 29 cyclopentadiene and 287 isoprene and 189 phenanthrene-1, 4-diones and 50 p-benzoquinone see 1,4-benzoquinone 332 o-benzoquinones 89 4-benzothiopyranone 106 benzylamine 149, 261 N-benzylideneaniline 264 benzyl isocyanide 149 N-benzyl-N-methallyl acrylamide 191 a-benzyloxyacetaldehyde 123 5-benzyloxymethylcyclopentadiene 112, 116 benzyl vinyl ether 146, 235 benzyne 55, 56 see also arynes bicyclospirolactone 209 1,10 -binaphthalene 64 2,3-bis(bromomethyl)benzo[b]thiophene 46 2,3-bis(chloromethyl)thiophene 46 bisdialine 64 bismuth(III) chloride 136 bismuth(III) triflate 294 bis(oxazoline) 132 bisphenylendiol 199 bis-o-quinodimethanes 47 bis-silanes, allylic 122 1,2-bis(triphenylphosphino)ethane 126 boron halides 36, 114 boron trifluoride 99, 106 bovine serum albumin (BSA) 180 bromoacrolein 133 2-bromo-2-cycloalkenones 130 bromo furylethers 8 3-bromo-indan-1-ones 56 bromoindanone 53 3-bromo-2-pyrone 41 N-bromosuccinimide 53 buckminsterfullerene (C60) 45, 228 butadiene 32, 118, 257 1,3-butadiene 33, 100, 102, 148, 229, 287 cycloalkenones and 23 ethene and 5, 12, 29 methylsubstituted 185, 252, 261 n-butyl acrylate 178, 288 t-butylglyoxylate 215 N-butylmaleimide 177 t-butyl methyl ether (TBME) 167 C-2 vinyl glicals 49 b-cadinene 102 camphor 73 Index camphorsulfonic acid (CSA) 224, 270, 271 carbazoles 59, 60, 62, 63 4-carbethoxy-trans-1,3-butadiene-1carbamate 184 (E)-1-carboalkoybutadienes 208 carbodienophiles, cycloadditions with 208±213 carbodiimides 9 carbon Diels±Alder reactions 29±66, 79, 100±121 2-carboxyethylnorbornadiene 20t 3-carbomethoxy-2-pyrone 126 catalysis 126, 144, 172, 185±190, 281, 284 antibody 183±185, 261±267 micellar 176±179, 198 proteins and enzyme 180±183 catalysts 114±122, 126, 128, 223, 279 catechols 182 cetyltrimethylammonium bromide 176, 177, 178, 179, 282 chaparrinone 255, 256 2-chloro-tropone 226 para-chlorophenol 276±278 chlorothricolide 1, 78, 211 citraconic anhydride 231, 274 1,3-Claisen rearrangements 295 clays 143, 144, 195 cobalt catalysts 126, 128 compactin 76, 123 condensation reactions 34, 251, 268 Cope elimination 63 copper didodecyl sulfate 177 Corey lactone 112 (/ )-criptopleurine 291 N-crotonyl oxazolidinone 133 crotonaldehyde 115 18-crown-6 ether 47 [12]-cyclacene 218 cycloadditions 24, 99, 100±106, 205, 268 cycloalkenones 23, 91, 109 cycloadditions of 100±106 a,b-unsaturated 209, 271 cyclodextrins 170 cyclohex-1-ene-1,6-dicarbaldehydes 40 cyclohexadiene 37±40, 144, 148, 164, 223±225 Index 1,3-cyclohexadiene 9, 88, 128, 223, 253, 287 cyclohexanones 30 cyclohexene 29, 119, 276 cyclohexenediols 36 2-cyclohexen-1-one 211, 224 cyclooct-2-en-1-ones 102 1,4-cyclopentadien-1-ol 226 cyclopentadiene 37±40, 146, 149t, 154, 169, 189, 262, 292 aldehydes and 71, 108, 118, 121, 135 N-alkyl maleimides and 253 p-benzoquinone and 287 N-benzyl-N-methallyl acrylamide and 191 catalysts and 109, 148 citraconic anhydride and 274 diethyl fumarate and 173, 285 dimethyl maleate and 279 ethyl acrylate and 170 glyoxylic acid and 185, 265 maleic anhydride and 14, 164 methacrolein and 147 methyl acrylate and 117, 147, 178, 255, 280, 282, 283t, 286 methylbenzoquinone and 269 methyl vinyl ketone and 144, 156, 170, 252 nonyl acrylate and 179 phenyl vinyl sulfide and 10 2-propen-1-ones and 177 quinones and 176 reactions in supercritical CO2 288 unsaturated esters and 194 cyclopentadienone 105, 220, 223, 276 4-cyclopentene-1,3-dione 164 2-cyclopentenone 210, 224, 226 cycloreversion 41, 269 Danishefsky's diene 51, 123, 167, 187, 210, 223, 264, 293 decalines 76, 196 dehydro aspidospermidine 40 5,6-dehydro-4H-1,3-thiazine 131 deltacyclenes 127 3-deoxy-D-manno-2-octulosonic acid 258 11-deoxyanthracyclines 207 12-deoxyphorbol acetate 233 Dess-Martin periodinane reagent 74 2,6-di-tert-butylpyridine 120 333 3,5-di-tert-butyl-o-benzoquinone 83 diastereofacial selectivity 101, 102, 104 diastereoisomers 207 (S,S)-diazaaluminolidine 116 dibenzofurans 59 dibenzothiophenes 59 dibromo-o-quinodimethane 218 dichloroisopropoxytitanium(IV) 119 dichloromethane 109, 113, 149, 157, 168, 189, 192, 230, 267 dicyanoacetylene 229 1,1-dicyanoethylenes 213 didehydrohomoiceane 128 Diels±Alder reactions of acylnitroso compounds 172t in aqueous medium 251±267 base-catalyzed 190 biocatalyst-promoted 180±185 catalyzed 144, 185±190, 261±267 cationic 128±130 consecutive 2, 20, 21 diastereoselective 199, 244, 255t domino 2, 20, 198 enantioselective 135, 289 high pressure 205±249, 267 inorganic solid-surface-promoted 143±149 ionic 5±10, 192, 200, 295 Lewis acid catalyzed 99±142 micelle-promoted 174±179 microwave-assisted 158±163, 195, 196 in molecular cavities 170±173 multiple 20±22 in non-aqueous polar systems 268±281 normal 122±123 pericyclic 4±5, 12 photo-induced 163±169 radical 5±10 regioselectivity of 12, 22, 23±24, 148, 175, 176, 198, 288t repetitive 245 retro 15±18, 35, 261, 290 stereoselectivity 24±25 of surfactant reagents 174±176 tandem 20, 21 thermal 5, 29±98, 162, 176, 214 ultrasound-assisted 154±158, 195 334 Diels±Alder reactions (contd ) uncatalyzed 252±261 using resin-anchored reagents 149±153 Diels-Alderase 181, 184 dienes 2, 3, 15, 16, 25, 148 across-ring 64±66 acyclic 36, 102 heterocyclic 40±42, 110±112 inner-outer ring 49±64, 219±223 inner-ring 191, 223±236 open chain 29±37, 191, 208±217 outer-ring 43±48, 217±219 stereochemistry of substituents 24 sulfinyl groups and 112±114 surfactant 176 tropones as 226±229 unsymmetric 10, 23 dienophiles 3±4, 5, 8, 12, 15, 44, 67, 101 acetylenic 43, 49, 57 carbonyl-containing 109, 115 heterocyclic 106±108 imino 137 olefinic 43 reactions with dienes 191 reactivity of neutral 9 stereochemistry of 25 sulfinyl groups and 112±114 surfactant 176 unsymmetric 10, 23 4,4-diethoxybut-2-ynal 40 diethylaluminum chloride 126 diethyl fumarate 170, 173, 285 diethyl maleate 285 N, N-diethyltryptamine-N-oxide 63 1,2-difluoro-1-chlorovinylphenylsulfone 196 dihydrocannivonine 262 9,10-dihydrofulvalene 80 dihydropyranes 123, 124 dihydropyranones 37 4-dihydropyranones 122, 123 dihydropyrans 122 3,4-dihydro-2H-pyrans 242 dihydropyridines 239 dihydropyridinones 240 dihydro-4-pyridones 187 dihydropyrones 90 Index dihydrothiopyrans 123 3,4-dihydrovinylnaphthalenes 53, 221 dihydrovinylphenanthrenes 55, 221 diiodosamarium 110 diisopropylethylamine 224 2,2-dimethoxyethylacrylate 128 2,5-dimethoxythiophene 230 dimethylacetylenedicarboxylate 32, 34, 40, 49, 50, 111, 127, 159 N,N-dimethylacylamide 184 dimethylaluminum selenide 71 dimethylamine 69, 79 dimethylaminobutadiene 31 1-dimethylamino-3-methyl-1-azadiene 156 1-dimethylamino-4-methyl-1-azadiene 155 2,5-dimethylbenzoquinone 275 1,3-dimethyl-1,3-butadiene 262 (E)-1,3-dimethylbutadiene 258 2,3-dimethylbutadiene 72, 107, 108, 115, 177, 273 2,3-dimethyl-1,3-butadiene 101, 160, 212, 213, 223, 253, 254t (E,E)-1,4-dimethylbutadiene 107 dimethylcyclobutane 102 dimethylcyclopropane 102 2,3-dimethylene-2,3-dihydrothiophene 43 dimethyl formamide 191 dimethyl fumarate 8, 32, 43, 44, 99 dimethylmaleate 32, 44, 279 2,3-dimethyl-5-oxocyclopent-1-ene-1carboxylate 210 dimethyltetrahydroindenone 223 a,a0 -dioxothiones 68 dipyridyltetrazine 81 diterpenes 154, 212, 232 divinylbenzene 115 divinylnaphthalenes 52 dodecane sulfonates 177 dodecyl maltoside 174 dodecyl sulfates 177 electrogenerated acid (EGA) 192 electron-withdrawing groups 34, 71 enaminoketones 69, 240 enantioselection 117, 135, 243, 289 endo adducts 171, 174, 177, 184, 190, 191, 208, 209 Index endo diastereoselectivity 36, 117 endo selectivity 74, 83, 192, 228, 266, 276 endo/exo diastereoselectivity 15, 178, 179, 236, 280, 288 enolethers 124, 126, 237 4-epi-pinguisone 211 epibatidine 90, 238 (/ )-epilupinine 291 1,4-epoxycadinane 112 ()-erysotrine 244 ethane 284 ethene 4, 5, 12, 29, 62 1-ethoxy-2-carbomethoxyacetylene 37 ethyl acetylenedicarboxylate 260 ethyl acrylate 32, 170, 279, 285 ethylene 29, 284 ethylene glycol 278 N-ethylmaleimide 184, 252, 253, 254t ethyl-4-methyl-3,5-hexadienoate 255 ethylpropiolate 34 ethylvinylether 208 ethyne 172, 227 ethynyltributyltin 68, 91 exo addition 14, 63, 145 exo adducts 15, 40, 174, 184, 228, 276 facial stereoselectivity 49, 73, 83, 292 Feringa-butenolide 74 ferrocenium hexafluorophosphate 114 flavones 85, 89 fluoboric acid 187 5-fluoronaphthoquinone 34 fluorophenols 33 FMO theory 12, 15, 22, 23, 24, 57 formaldehyde 261 Friedel-Crafts reactions 279 fullerene [C60] 36, 84, 87, 168, 224, 241 condensed aromatics and 193, 200 derivatization of 35, 67 o-quinodimethanes and 46, 47 fumaric acid 149 fumaronitrile 8 functional groups, protection of 252 furan 57, 113, 148, 170, 252, 269 furanamide 272 furanones 40 335 furans 40, 58, 89, 112, 229±234, 267 furfuryl fumarates 239 furylaldehydes 149, 151 glucopyranosil-1, 3-pentadiene 260 D-glucose 7, 37 D-glyceraldehyde 292 2-glycosylamino pyridines 17 glyoxal 158, 258 glyoxylic acid 185, 258, 264, 265, 294 graphite 160, 161, 196 Grub's ruthenium initiator 152 guanidinium chloride 252, 253 helicenebisquinones 219 helicenes 55, 56 hematoporphyrin 163, 169 hetero-Diels±Alder reactions 34, 66±73, 83, 122±126, 158 asymmetric 131, 133, 238 with heterodienophiles 213±214 intermolecular 240 intramolecular 79, 82, 171, 292 in supercritical CO2 287 heterocycles 57, 72, 82, 149, 213 heterodienes 66±70 heterodienophiles 66, 70±73, 213±217 hexadecyltrimethylammonium bromide 282 trans, trans-2,4-hexadiene 9 high-speed vibration milling (HSVM) 193 HOMO 22, 29, 57, 62, 67, 107 homo-Diels±Alder reactions 18±20, 126±128 homobarrelenones 226, 227 hydrindanones 101 hydrobenzosuberone 76, 101 hydrofluorenones 104 hydrophenanthrenones 212 hydroxamic acid 257 5-hydroxynaphthoquinone 155, 164 3-hydroxy-2-pyrone 190, 191t, 278, 293 3-hydroxytanshinone 195 o-hydroxythiophthalimides 68 2-hydroxytropone 226 1-hydroxyvitamin D3 235 336 iceane 81 imino Diels±Alder reactions 134, 270 5-iminopyrazoles 159 indanone 53, 227 inden-1-one 53, 56, 221 indeno[c]phenanthrenones 53 indium trichloride 134, 266, 293 indole 44, 63, 164 indolquinolines 9 intermolecular Diels±Alder reactions 1, 3, 116, 205, 240, 278 aqueous 290 Lewis acid catalysis 128 intramolecular Diels±Alder reactions 1, 3, 8, 74±83 of amino acid-derivative trienes 149 of furans 170, 197, 232 of furfuryl fumarates 239 high pressure 233 immonium ion based 291 microwave-assisted 163 of polyenones 270 tandem photooxidation 196 of trans-cycloalkenones 91 inverse electron-demand Diels±Alder reactions 3, 4, 23, 123±125, 126, 208 heterocycles and 68 intermolecular 216 Lewis acid catalyzed 109 2-pyrones and 234 iodine 191 ionic liquids 278±281 iron(III) 2-ethylhexaonate 124 isomerization 14, 107, 279 isooctane 282 isoprene 6, 104, 108, 115, 187, 287, 288 but-3-en-2-one and 279 catalysts and 118 dimethyl acetylenedicarboxylate and 274 4-isopropyl-2-cyclehexenone 102 maleic anhydride and 286 Nafion-H and 189 quinidine-5,8-dione and 106 zeolites and 148, 194 4-isopropyl-2-cyclohexenone 102 isoquinoline-5, 8-dione 106 isoquinolines 70, 106, 197 Index jatropholone A and B 232 Jencks postulate 184 (/ )-julandine 291 K-10 montmorillonite 143, 144, 145, 146, 161 ketals 271, 274 ketodeoxyheptulosonic acid 259 ketones 63, 109, 271, 274 lactams 191, 200 lactones 45, 271 lanthanide shift reagent-catalysis 126 lanthanide triflates 108, 109, 110, 251, 262, 264, 293 Lawesson's reagent 69 Lewis acid catalysts 37, 206, 209, 214, 268, 288 alkoxybutadienes and 73 exo-endo diastereoselectivity 15 high pressure and 205 norbornene derivatives and 38 olefinic acetals and 199 quinone-mono-ketals 212 surfactant combined 176, 177 zeolites and 148, 194 Lewis acids 23, 24, 99±142, 191, 230 coupling photolysis 167 in ionic liquids 279±281 Lanthanide triflates 293 ( )-menthol-aluminum 147 water-tolerant 251 lithium chloride 252, 253 lithium perchlorate 113, 295, 296 lithium perchlorate±diethyl ether (LP±DE) 268±273, 294 lithium perchlorate±nitromethane 273±274, 295 lithium trifluoromethanesulfonimide 274±276, 296 LUMO 22, 23, 24, 36, 107 (/ )-lupinine 291 2,6-lutidine 74, 123 macrocycles 217, 242 maleic acid 149 maleic anhydride 80, 145, 151, 164, 224, 243 Index anthracene and 99, 157, 160, 163 C-2 vinyl glical and 49 1, 3-cyclohexadiene and 287 cyclopentadiene and 14, 164 furan and 230, 231, 252 isoprene and 286, 288 2-methoxy-1,3-butadiene and 117 norboradiene and 18 polycycles synthesis 43, 81 tropone and 226 2-vinylthiophene and 58 maleimide 116, 117, 230 maleonitrile 8 malic acid 258 Mannich conditions 290 menthylacrylate 38, 145 l-menthylallyl-ether 38 metal ions, influence of 265 methacrolein 133, 147, 259 3-methallylcyclohexenone 90 methanol 8, 104, 155, 255 p-methoxybenzaldehyde 123 1-methoxybutadiene 208, 214, 215 1-methoxy-1,3-butadiene 104, 214, 238, 245 2-methoxy-1,3-butadiene 116, 117 methoxy carbonyl maleic anhydride 231 methoxy cyclohexadiene 180 6-methoxy-2,4-dihydro-1vinylnaphthalene 53 2-methoxy-4-isopropyl-tropone 226 2-methoxy-6-isopropyl-tropone 226 S-()-2-methoxymethyl pyrrolidine 30 2-methoxy-3-thiophenylbutadiene 12 1-methoxy-3-trialkylsilyloxy-1, 3butadienes 215 methoxytrimethylsilane 6, 128, 129 2-methoxytropone 226 methyl acrylate 8, 32, 43, 44, 235, 287 cyclopentadiene and 117, 147, 178, 255, 280, 282, 283t, 286 ionic liquids and 280 2-pyrone and 235 sulfinyldiene and 113 zeolites and 148 methylalumoxane 134 methylamine hydrochloride 264 methyl-5-aminofuroate 86 337 9-methylanthracene 168 2-methylbenzaldehyde 166, 196 methylbenzoquinone 269 2-methyl-1,4-benzoquinone 164 methyl cis-dihydrojasmonate 38 2-methyl furan 73 3-methyl-furfuryl alcohol 182 methylglyoxylate 72, 158 N-methylmaleimide 7, 276 methyl methacrylate 123 methyl-trans-4-methoxy-2-oxo-3butenoate 216 methyl palustrate 243 2-methyl-1,3-pentadiene 158 4-methyl-6-phenyl-5, 6-dihydro-2H-pyran 6 methylpropiolate 117 methyl propynoate 62 1-methyl-2-(1H)-pyridones 245 methylrhenium trioxide 266 methyl tanshinonate 195 4-methyl-1,2,3-triazine 126 methyl vinyl ketone 144, 156, 170, 255, 266 cyclopentadiene and 252 2-methoxy-3-thiophenylbutadiene 12 mevinolin 123 micelles 283 Michael reactions 7, 268 microemulsion 281±283 MMX force field calculations 62 monosaccharides 214 morpholinoacrylonitrile 197 nafion-H 189 naphthalenes 110, 212 naphthanilides 211 naphthols 41 1,4-naphthoquinone 161, 180, 195, 224 cis-3-neopentoxyisobornyl acrylate 145 nickel catalysts 127 nickel-cyclooctadiene 18, 19t, 20t niobium 132 nitroalchenes, a,b-unsaturated 274 nitroalkenes 30, 159 nitrobenzene 162 nitrocyclohexanones 30 nitrogen heterocycles 72, 149 nitromethane 114, 273±274, 295 338 nitrostyrene 51, 237, 273 norbornadiene 18, 37, 126, 127, 291 norbornanes 37 norbornene 38, 119, 226 norbornenones 37 normal electron-demand Diels±Alder reactions 3, 4, 23, 29, 69, 234 (/ )-occidentalol 17 octahydrobenzazepinones 152 octalones 101 orthoesters, ketals of 271 7-oxabicyclo[2.2.1]heptadiene 227 7-oxabicyclo[2.2.1]heptene 40 1-oxadecalones 90 1-oxa[4.4.4]propella-5, 7-diene 224 oxasilacyclopentanes 89 oxazaborinane 118 1,2-oxazines 257 oxazoborolidinone 147 (E)-4-oxobutenoate 124 oxoenaminoketones 69 2-oxopropyl acrylate 6, 128 p-face-selectivity 40, 224 p-p donor±acceptor interactions 121, 185 palasonin 231 palitaxel 231 pentacene 193 (E)-2,4-pentadienyl ammonium chloride 289 pentahelicenes 65 pentamethylcyclopentadiene 10 perfluorooctanonitrile 213 phenanthrene-1,4-diones 50 1,4-phenanthrenequinones 239 phenanthridinone 134 phenols 32, 182, 281 N-phenyl maleimide 43, 44, 144±145 phenylacetylene 168 (E)-1-phenyl-1,3-butadienes 213 cis-1-phenyl-1-cyclohexene 25 phenylglyoxal 264 (2R)-N-(phenylglyoxyloyl)bornane-10, 2-sultam 238 N-phenylmaleimide 80, 195, 226, 236, 245, 276 1-oxa[4.4.4]propella-5, 7-diene and 224 Index Lewis acid catalysis 73 methyl palustrate and 243 microwave-assisted reactions 161 phenylnitrocyclohexenes 51 phenylsulfinylselenylchloride 72 (E)-1-phenylsulfonyl-3-alken-2-ones 133 N-phenylsulfonylindole-3-carbaldehyde 63 phenyltriazolinedione 73, 80 4-phenyl-1,2,4-triazoline-3,5-dione 287 4-phenyl-4-trifluoromethyl-2-cyclohexen-1one 51, 223 1-phenyl-4-vinylpyrazole 58 1-phenyl-5-vinylpyrazole 58 phorbols 233, 234 2-piperidinobutadienes 106 piperylene 24, 275 (E)-piperylene 101, 104, 106, 107, 209, 212 polycyclic cage compounds 80 polymers 232, 284 porphyrin 170 (S)-prolinol 133 propane 284, 286, 287 2-propanol 282 2-propen-1-ones 177 2,3-di-n-propylbutadiene 36 prosolanapyrone 181, 199 prostatin 233 pumiliotoxin 171, 257 pyranes, synthesis of 123±125 4-pyranones 122 2H-pyran-2-ones 161, 195 pyrano-[4,3-b]-pyrrole 44 pyridazines, 3,5-disubstituted 91 pyridines 68, 79, 123 pyridones 91, 234±236 pyrimidones 91 2-pyrone 41, 234, 235, 236, 239 pyrones 90, 122±123, 126±128, 181, 199, 234 pyrrole 2, 3-quinodimethane 44 pyruvaldehyde 258, 264 pyruvic acid 258 quassinoids 255 o-quinodimethanes 43, 46, 47, 218 quinoline 134 quinoline-5, 8-dione 106 Index quinolizidine 291 quinone 33, 88, 109, 176 o-quinone 154, 155, 182, 195 quinone-mono-ketals 212, 241 rare earth metals 108 reaction medium, choice of 251 reactivity-selectivity principle 99 rearrangements, sigmatropic 268 regiochemistry 10±12 regioselectivity 36, 42, 72, 99 s bonds 5, 15, 18, 23 Salvia miltiorrhiza 154, 195 scandium triflate 108±110, 120, 293 scandium(III) perfluorooctanesulfonate 134 secohexaprismane 81 selenides, allyl alkenyl 85 selenoaldehydes 71, 85 selenoketones 85 self-Diels±Alder reactions 148 sesquiterpenes 77, 210 [1, 3]-sigmatropic hydrogen shifts 159 silica gel 115, 133, 143, 146, 147, 161 siloles 234 2-siloxybutadiene 107 o-silylenol ethers 136 silyloxydienes 151, 194 silylthioaldehydes 70 silyl triflate 151, 194 sodium dodecyl sulfate 174, 177, 178, 282 solanapyrones 181, 199 solvents 207, 252, 278, 284, 286 sonochemical effect 156, 195 stereochemistry 12±15 stereoselectivity, of cycloadditions 99 steroids 53, 212 styrene 49±51, 88, 219, 276 sugar allyltins 240 sulfinimides, a,b-unsaturated 239 sulfinylacrylate 113 sulfolenes, thermolysis of 44 N-sulphinylphosphoramidates 136 sultones, a,b-unsaturated 88 supercritical fluids 284±289, 296 swainsonine 171, 257 339 tanshindiol B 195 tantalum 132 tellurides 85 telluroaldehydes 85 temporary metal connection strategy 193 terpenoids, bioactive 135 tetra-n-butylammonium fluoride 16 tetracene 193 tetrachlorocyclopropene 32 tetrachlorothiophene dioxide 184 tetracyanoethylene 80 tetrafluorobenzyne 229 tetrahydrobenzofurans 57 tetrahydrocarbazoles 63, 64 tetrahydrofuran 7, 8, 16, 115, 168, 255, 260 tetrahydropyridines 237, 239, 264 tetrahydrothiopyrans 79 tetramethylbisdialine 65 tetraphenylporphyrin 163, 169 1-thiabuta-1,3-diene 133 1,3,5-thiadiazines 67 thieno-o-quinodimethanes 46 thioaldehydes 71 thioazadienes 67 thiochromanones 69 thioketones 123 thiones 68 thiophene 40, 57, 229±234 (E)-2-thiophenylbutadiene 90 thiopyrans 69, 123 o-thioquinones 68 D-threoninals 245 p-toluene-sulfonic acid 211 p-toluensulphonylisocyanate 72 tosylimine 72 transition metal catalysts 18, 114±115, 126, 127, 128, 137 trehalose 260 2-trimethylsilyloxy-1,3-butadiene 211 trialkylamines 281 triazines 70, 126, 237 tricarbonyl (tropone) iron 213 triethylamine 7, 8, 36, 56, 164 triflic acid 6, 151, 185, 186t trifluoroacetic acid 149, 151, 270, 271 1-trifluoro-3,4-dihydronaphthalene 223 1,1,1-trifluoroethanol 255 340 Index trifluoromethanesulfonic acid see triflic acid trifluoromethyl diethylphthalate 34 a-trifluoromethyl styrene 51, 223 trifluoromethylethylbenzoate 34 trimethylaluminum 117 trimethyl orthoformate 151 cis-1,2,6-trimethylpiperidine 120 1-(-trimethylsiloxy)-1, 3-butadiene 154 trimethylsilylimines 67 3-(trimethylsilyl)propynoates 88 trimethylsilyltriflate 6, 115, 128 1,3,3-trimethyl-2-vinylcyclohexene 244 tris-(p-bromophenyl)aminium hexachloroantimonate 9, 157 tris-(trimethylsilyl)silane 8 tropolone 226 tropone 32, 213, 226±229 (/ )-turmerone 17 tyrosinase 182, 183t (S)-tyrosine 133 vinylbenzofurans 57, 59, 60 vinylbenzo[b]thiophenes 60 vinylboranes 36 vinylcyclohexene 148, 154, 155 vinylethers 68, 124, 126, 133, 264 vinylfurans 56, 57, 58 vinylindole 60, 62, 63, 64, 87 vinylnaphthalenes 49±54, 219, 220 vinyloxocarbenium ions 188, 199 3-vinylphenanthrene 52 vinylpyrazoles 58, 159 1-vinylpyrene 52 vinylthioethers 264 vinylthiophenes 56, 58 Ugi reaction 149 zeolites 143, 146, 147±148, 194 zinc chloride 223 zinc didodecyl sulfate 177 vinylallenes 90 water 197, 282, 284, 285 Wittig reaction 63 Woodward-Hoffmann rules 24 ytterbium catalysts 126 The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 1 1.1 Diels±Alder Reaction: General Remarks INTRODUCTION The Diels±Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon± carbon, carbon±heteroatom and heteroatom±heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1]. Scheme 1.1 illustrates two examples: the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels±Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of ( )chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels±Alder cycloaddition [3]. Ph Ph O + O H O PhMe, Rfx O 3 h, 80% H O O 1 OSPDBT OSPDBT COOH t -Bu O + O O O PhMe, 120 ⬚C O O O O O O OH t-Bu O O O H H Me3Si OMOM Me3Si H 2 Scheme 1.1 H OMOM 3 OH 2 Introduction To rapidly construct complex structures, a recent synthetic strategy uses the Diels±Alder cycloaddition in sequence with another Diels±Alder reaction or with other reactions without isolating the intermediates (domino, tandem, cascade, consecutive, etc., reactions) [4±6]. Scheme 1.2 illustrates some examples. Domino Knoevenagel hetero -Diels−Alder reactions [7] O t-Bu O CHO + O N N Ph t -Bu EDDA, MeCN Rfx, 16 h, 94% H t -Bu H N O O N N N O Ph Ph Cascade Diels−Alder acylation reactions [8] OSMDBT OSMDBT O N + THF, 50% Cl 2 h, −78 ⬚C, 24 h, 0 ⬚C Domino Diels−Alder reactions [9] Ph O + H 100 O Ph ⬚C N Cl H O H O N H O O Ph Ph Ph Ph Scheme 1.2 The main purpose of this chapter is to introduce the various aspects of the Diels±Alder cycloaddition and the terminology employed. Since its discovery in 1928 [10], more than 17 000 papers have been published concerning synthetic, mechanistic and theoretical aspects of the reaction and about half of these have appeared in the last decade. The classical Diels±Alder reaction is a cycloaddition between a conjugated diene and a second component, called dienophile, which has at least a p bond (Equation 1.1). When one or more heteroatoms are present in the diene and/or dienophile framework, the cycloaddition is called a hetero-Diels±Alder reaction. 1:1 Diels±Alder Reaction: General Remarks 3 The reaction is classified as a [p 4s p 2s ] cycloaddition; 4 and 2 identify both the number of p electrons involved in the electronic rearrangement and the number of atoms originating the unsaturated six-membered ring. The subscript s indicates that the reaction takes place suprafacially on both components. There are other [p 4s p 2s ] reactions, and therefore it is the term Diels±Alder which specifies this particular type of reaction. The Diels±Alder reaction can be intermolecular or intramolecular and can be carried out under a variety of experimental conditions that will be illustrated in detail in the following chapters. 1.2 DIENE AND DIENOPHILE A great variety of conjugated dienes have been used and many of them have been collected and classified [1a]. Table 1.1 illustrates some examples. Conjugated dienes react providing that the two double bonds have or can assume a cisoid geometry (Equation 1.2). A transoid diene (Equation 1.3) would give an energetically very unfavorable six-membered ring having a trans double bond. Cyclic dienes are generally more reactive than the open chain ones. The electronic effects of the substituents in the diene influence the rate of cycloaddition [11]. Electron-donating substituted dienes accelerate the reaction with electron-withdrawing substituted dienophiles (normal electron-demand Diels±Alder reaction) (Equation 1.4) [12], whereas electronwithdrawing groups in the diene accelerate the cycloaddition with dienophiles having electron-donating groups (inverse electron-demand Diels±Alder reaction) Table 1.1 Representative dienes Open chain Outer ring O OSiMe3 Inner-outer ring Across ring Inner ring O O N OMe O O O O O O O O O O O 4 Pericyclic Diels±Alder Reaction (Equation 1.5) [13]. Diels±Alder reactions which are insensitive to the substituent effects in the diene and/or dienophile are classified as neutral (Equation 1.6) [14]. reactive dienes unreactive dienes O O R1 R2 + 1:3 R1 R2 AlCl3 PhMe R3 1:2 1:4 R3 H R1, R2, R3 = H, Me O O CO2Et OEt + CO2Et 90 ⬚C, 24 h 95% OEt H Ar O Ph O Ar 1:5 + Ar1 Ar 60 ⬚C Ph PhMe Ph Ar Ph Ar 1 1:6 Ar = C6H4Y (Y = H, p-OMe, p-NMe2) Ar1 = C6H4Y (Y = H, p-OMe, p-NMe2, p-Cl, p-NO2, m-NO2) Dienophiles are molecules possessing a double or triple bond. They are more numerous and more variegated than dienes [1]. Typical dienophiles are illustrated in Table 1.2. The simplest dienophile, ethene, is poorly reactive. Electron-withdrawing and electron-donating groups, on the carbon atom double bond, activate the double bond in normal and inverse electron-demand Diels±Alder reactions, respectively. 1.3 PERICYCLIC DIELS±ALDER REACTION The Diels±Alder reaction is a pericyclic cycloaddition when bond-forming and bond-breaking processes are concerted in the six-membered transition state Diels±Alder Reaction: General Remarks Table 1.2 5 Representative dienophiles Cyclic Acyclic O CHO COMe O O CN O (NC)2 (CN)2 MeO2CCH CHCO2Me O O HC CO2Me N N Me2C S Ph N O O O O H2C C CHMe N N Ph O ArN NCN O S S O O OEt O O (Equation 1.7). A concerted synchronous transition state [15] (the formation of new bonds occurs simultaneously) and a concerted asynchronous transition state [16] (the formation of one s bond proceeds in advance of the other) have been suggested, and the pathway of the reaction depends on the nature of the reagents and the experimental conditions [17]. O + O O O H O O O O H 1:7 O Most Diels±Alder reactions, particularly the thermal ones and those involving apolar dienes and dienophiles, are described by a concerted mechanism [17]. The reaction between 1,3-butadiene and ethene is a prototype of concerted synchronous reactions that have been investigated both experimentally and theoretically [18]. A concerted unsymmetrical transition state has been invoked to justify the stereochemistry of AlCl3 -catalyzed cycloadditions of alkylcyclohexenones with methyl-butadienes [12]. The high syn stereospecificity of the reaction, the low solvent effect on the reaction rate, and the large negative values of both activation entropy and activation volume comprise the chemical evidence usually given in favor of a pericyclic Diels±Alder reaction. 1.4 IONIC AND RADICAL DIELS±ALDER REACTIONS Conjugated cations, anions and radicals can give the Diels±Alder reaction. In such a case, the two s bonds are formed in two separate steps (stepwise 6 Ionic and Radical Diels±Alder Reactions mechanism) and the cycloaddition is not pericyclic [19]. Both cationic and cation radical Diels±Alder reactions were recently reviewed [20]. Extensive studies by Gorman and Gassman have shown that an allyl cation can be a 2-electron component in a normal electron-demand cationic Diels± Alder reaction and, since a carbocation is a very strong electron-withdrawing group, the allyl cation is a highly reactive dienophile [19a, 21]. Tetraene 4 (Scheme 1.3), when treated with 40 mol % of triflic acid in methylene chloride at 23 8C for 1 h, gives the adducts 5 and 6 in a 1:1 ratio as the main reaction products. The formation of these adducts has been justified [21] by a stepwise mechanism that requires an initial reversible protonation of 4 to produce the allyl cation 7, which then cyclizes to 8 and 9 in a non-reversible process. Deprotonation of 8 and 9 gives 5 and 6, respectively. H CF3SO3H, DCM H + −23 ⬚C, 1 h H H 5 6 4 H −H −H H H H + H H 8 7 H 9 Scheme 1.3 Other examples that involve intermediate allyl cations are illustrated in Scheme 1.4. The cationic palladium(II) complex [Pd(dppp)(PhCN2 BF4 2 coordinates the carbonyl oxygen of benzaldehyde and the activated carbonyl carbon attacks the isoprene, forming the allyl cation 10 which then cyclizes to give the 4-methyl-6-phenyl-5,6-dihydro-2H-pyran [22]. 2-Oxopropyl acrylate 11, in the presence of trimethylsilyltrifluoromethane sulfonate (TMSOTf ) and methoxytrimethylsilane (MeOSMT), generates the cation 11a which is an efficient dienophile that reacts easily with the cyclohexadiene to give the Diels± Alder adduct in good yield [23]. Diels±Alder Reaction: General Remarks 7 O Ph Ph Pd2+, CHCl3, 50 ⬚C, 20 h, 67% H O Ph O Pd2+ Ph O H Pd2+ 10 O O O TMSOTf O OMe MeOSMT, DCM, −45 ⬚C 11 h, 89% O CO2CH2COCH3 11 11a Scheme 1.4 Anionic Diels±Alder reactions have been studied less extensively with the interest having been focused mainly on the cycloaddition of enolates of a,bunsaturated ketones with electron-poor olefins [24] (Equations 1.8 and 1.9). These reactions are fast and stereoselective and can be regarded as a sequential double Michael condensation, but a mechanism involving a Diels±Alder cycloaddition seems to be preferred [24b,f, 25]. O O Li CO2CH3 H CO2CH3 H CO2CH3 1:8 H LDA −23 ⬚C, 2 h, 90% −23 ⬚C, 1 h OLi O O Li EtO2C O EtO2C O LDA −20 ⬚C, 2 h, 45% OEt H O 1:9 The first evidence of an anionic Diels±Alder reaction was given by Rickborn [25a]. The reaction of anthrone with N-methylmaleimide in CHCl3 or THF occurs with low yield [26] (Equation 1.10), while in DMF or in the presence of catalytic amounts of amine (Et3 N, Py) the reaction is completed in a few minutes [25]. 8 Ionic and Radical Diels±Alder Reactions The cycloaddition is ascribable to the oxyanion of hydrogen-bonded enolate (ArO ---HNEt3 ) rather than to the hydrogen-bonded enol (ArOH---NEt3 ). An enantioselective version of the reaction was achieved by using a homochiral amine [27]. Similarly the reactions with less reactive dienophiles such as dimethyl fumarate, fumaronitrile, maleonitrile and methyl acrylate give the Diels±Alder adducts quantitatively when the cycloadditions are carried out in THF or CHCl3 in the presence of Et3 N, while in MeOH Michael adducts were isolated. Experimental evidence supports the hypothesis that the base-catalyzed cycloadditions of anthrone with dienophiles are concerted Diels±Alder processes [25b]. 68 h, 25 ⬚C CHCl3, 14% O O NMe + O O NMe HO O OH 1:10 15 min, 25 ⬚C DMF, 100% Radical Diels±Alder reactions have been used mainly to synthesize polycyclic molecules. These reactions, like those that involve cations and anions as components, proceed quickly but generally do not give high yields. Thus, the tricyclic enone 14 is the result of an intramolecular Diels±Alder reaction of quenched vinyl radical intermediate 13 obtained by treating the iododienynone 12 with ntributyltin hydride/2,20 -azobisisobutyronitrile (AIBN) [28] (Equation 1.11). I H AIBN n-Bu3SnH H 80 ⬚C, 8 h, 22% O H H O O O 12 13 1:11 14 Heteropolycyclic compounds were obtained [29] by treating bromo furylethers with tris-(trimethylsilyl)silane (TTMSS) in hot toluene containing a catalytic amount of AIBN (Equation 1.12). Br R O O H TTMSS AIBN, PhMe 85 ⬚C, 16−26% R O Br O + R O O 1:12 R = H, Me, Cy R O O Diels±Alder Reaction: General Remarks 9 Wang recently reported [30] that thermolysis of carbodiimides 15 (Scheme 1.5) in aromatic solvents is an efficient route to indoloquinolines 18 used as precursors for synthesizing naturally occurring alkaloids [31]. The cyclization is thought to occur through a two-step biradical Diels±Alder reaction that gives 17, which then tautomerizes to 18. R R N C 130-160 ⬚C N N N 15 16 R R N N N N H 18 17 R H Me Pr t-Bu Ph MeSi Yield (%) 16 77 89 76 91 86 Scheme 1.5 The reactivity of neutral dienophiles is greatly increased by converting them to the corresponding cation radicals because these highly electron-deficient species can then react readily with dienes. The dimerization of 1,3-cyclohexadiene gives 30% adduct after 20 h at 30 8C [32]. In the presence of a catalytic amount of tris(p-bromophenyl) aminium hexachloroantimonate (Ar3 N SbCl6 ; Ar pBrC6 H4 ) in CH2 Cl2 at 0 8C, the cyclodimerization occurs in 15 min with 70 % yield with a greater diastereoselectivity (endo=exo 5:1) than that observed under thermal conditions (Equation 1.13) [33]. Ar3N SbCl6, DCM 0⬚C, 15 min, 70% H H 1:13 The first studies on cation-radical Diels±Alder reactions were undertaken by Bauld in 1981 who showed [33a] the powerful catalytic effect of aminium cation radical salts on certain Diels±Alder cycloadditions. For example, the reaction of 1,3-cyclohexadiene with trans, trans-2,4-hexadiene in the presence of Ar3 N% is complete in 1 h and gives only the endo adduct (Equation 1.14) [33]. 10 Regiochemistry Ar3N SbCl6 + 1:14 DCM As a continuation of these studies, Bauld recently reported evidence of a stepwise mechanism in the cation-radical Diels±Alder reaction of phenyl vinyl sulfide with cyclopentadiene [34, 35] (Scheme 1.6). + + Ar3N SPh Ar3N SPh + SPh SPh Ar3N SPh + Ar3N SPh SPh Scheme 1.6 An analogous stepwise mechanism was also proposed by WoÈhrle [36] for the cation-radical-initiated cycloaddition of electron-rich allenes with pentamethylcyclopentadiene in the presence of tris (p-tolyl) aminium hexafluoroantimonate (TTA% SbF6 ) (Equation 1.15). R + Me C C C H Ar Me TTA, 0 ⬚C, 5 min 2,6-t -Bu2Py Ar H 1.5 R Ar + Me H 1:15 R REGIOCHEMISTRY When an unsymmetrical diene reacts with an unsymmetrical dienophile, two regioisomer adducts can be formed depending on the orientation of the substituents in the adduct [37] (Equations 1.16 and 1.17). Diels±Alder Reaction: General Remarks 11 The regioisomer adducts are usually named by using the classic nomenclature of disubstituted benzenes: ortho, meta and para. This descriptive method, however, encounters difficulties with adducts as simple as those from disubstituted dienes and dienophiles. Thus a new nomenclature has been proposed [38]. The original diene atoms forming the six-membered ring are numbered one through four, the lowest number being closest to the more electron-withdrawing group bonded to the atom of the original dienophile. The positional relationship of the substituents is now identified by a simple number set within a bracket followed by the word adduct. + CO2Me CO2Me 1 2 3 + 4 + CO2Me 1 90% 98% 3 4 2 1 CO2Me 1:16 10% 2% + 2 1 3 4 CO2Me para, [3] adduct 20 ⬚C 20 ⬚C, AlCl3 4 2 meta, [4] adduct ortho, [1] adduct 20 ⬚C 20 ⬚C, AlCl3 3 CO2Me meta, [2] adduct 70% 95% 1:17 30% 5% The description of the regiochemistry of the cycloaddition products of dienes that have two or more dissimilar substituents may require incorporation of their name in the new notation (Equations 1.18 [38] and 1.19 [39]). O O PhMe, AlCl3 + 40 ⬚C, 15 min, 85% 2 1 3 4 1:18 [1,3] adduct PhS COMe + MeO 70 ⬚C, 24 h 75% PhS MeO 3 2 4 PhS 2 1 + COMe MeO 3 80% [2 (OMe), 3 (SPh)] 1 COMe 4 1:19 20% [2 (SPh), 3 (OMe)] The regioselectivity of the Diels±Alder reaction depends on the number and nature of substituents on diene and dienophile and on the reaction conditions (catalyst, temperature, pressure, solvent, etc.). Generally, 1- and 2-substituted 12 Stereochemistry butadienes react with monosubstituted dienophiles to give mainly ortho and para adducts, respectively. When two different substituents are present on the diene, one works as regiodirector and controls the regiochemistry of the reaction. Table 1.3 illustrates the main regioisomer obtainable in the cycloaddition of disubstituted 1,3-butadienes with monosubstituted ethenes [40] where R1 is the regiodirector group. Thus, for example, in the cycloaddition of 2-methoxy3-thiophenylbutadiene with methylvinylketone, one can foresee that the main regioisomer will be the 1-thiophenyl-2-methoxy-4-acetyl-cyclohexen-1-ene because the SPh is the regiodirector group. In fact, this regioisomer is the main reaction product (80 %) [39]. Exceptions to the ortho±para rule have been observed, so the prediction of the regiochemistry is still a stimulating challenge. The regioselectivity of simple Diels±Alder reactions has been explained on the basis of the electronic effects of the substituents which orient the attack of reagent species by generating partial positive and negative charges in the diene and dienophile. Generally, the more powerful the electronic effect of the substituents, the more regioselective the reaction. Although this explanation has some merit, the FMO theory [41] and the matching of complementary reactivity surfaces of the diene and dienophile [40] give a better explanation. Table 1.3 Regioselectivity of Diels±Alder reactions of disubstituted 1,3-butadienes with monosubstituted ethenes (RCHCH2 ) R1 R2 1.6 R1 R1 R1 R R2 R R2 R2 R1 R1 R2 R2 R1 R2 R1 R2 R1 R2 Me Me Me Me Bn SPh Ph OEt OAc Cl NHCOCH3 OMe Me Ph NHCO2 Et NHCO2 Bu OAc SPh SiEt3 Me Me SPh Et OAc Ph SPh SPh SPh Cl Me Me OMe OAc Me R STEREOCHEMISTRY Pericyclic Diels±Alder reactions are suprafacial reactions and this manner of bond formation preserves in the cycloadduct the relative stereochemistry of the substituents at C1 and C4 and at C1 and C2 of the parents diene and dienophile, respectively (Scheme 1.7). The relative stereochemistry of the substituents in the Diels±Alder Reaction: General Remarks CO2Me 13 CO2Me CO2Me MeO C 2 CO2Me CO2Me CO2Me + CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me Scheme 1.7 CO2Pr + 80 ⬚C CO2Pr R R 42.7% CO2Pr endo-meta endo-ortho CO2Pr 6.3% R R 44.5% CO2Pr exo-meta exo-ortho R = CO2Pr Scheme 1.8 6.5% 14 Stereochemistry O R3 R4 + R2 R1 R2 H O R4 R1 R1 R3 H R2 R4 R3 H R1 O R4 R4 R3 O R2 endo-syn R3 R2 H R1 O endo-anti R2 H O R1 R R4 3 R4 H R1 R3 O R4 R3 R4 H R1 O R2 R2 O exo-anti exo-syn H R1 R2 R3 Scheme 1.9 new stereogenic centers of the adduct is fixed by two possible suprafacial approaches named endo and exo. The endo mode of attack is the spatial arrangement of reactants in which the bulkier sides of the diene and dienophile lie one above the other, while in the exo mode of addition the bulkier side of one component is under the small side of the other. If one also considers the regioselectivity and the face selectivity of the reaction, a considerable number of isomers can, in principle, be produced. Schemes 1.8 and 1.9 give two general pictures. However, the Diels±Alder cycloaddition is known to be a highly selective reaction, and consequently only one or a very limited number of isomers are actually obtained. The exo addition mode is expected to be preferred because it suffers fewer steric repulsive interactions than the endo approach; however, the endo adduct is usually the major product because of stabilizing secondary orbital interactions in the transition state (Scheme 1.10). The endo preference is known as Alder's rule. A typical example is the reaction of cyclopentadiene with maleic anhydride which, at room temperature, gives the endo adduct which is then converted at Diels±Alder Reaction: General Remarks 15 200 8C to the thermodynamically more stable exo adduct through a retro Diels± Alder reaction followed by re-addition (Scheme 1.10). The generally observed endo preference has been justified by secondary orbital interactions, [17e, 42, 43] by inductive or charge-transfer interactions [44] and by the geometrical overlap relationship of the p orbitals at the primary centers [45]. The exo±endo diastereoselectivity is affected by Lewis acid catalysts, and the ratio of two stereoisomers can be explained on the basis of the FMO theory [17e, 46]. O O + O O O O O O endo H exo O O H O O O H O H O Scheme 1.10 1.7 RETRO DIELS±ALDER REACTION The Diels±Alder reaction is reversible and the direction of cycloaddition is favored because two p bonds are replaced by two s-bonds. The cycloreversion occurs when the diene and/or dienophile are particularly stable molecules (i.e. 16 Retro Diels±Alder Reaction formation of an aromatic ring, of nitrogen, of carbon dioxide, of acetylene, of ethylene, of nitriles, etc.) or when one of them can be easily removed or consumed in a subsequent reaction (Equations 1.20 and 1.21). COPh N EtO2C CO2Et CO2Et 190 ⬚C N CO2Et N ∆ N − N2 HC CH + 54% 1:20 COPh CO2Me DMAD 1:21 CO2Me The retro Diels±Alder reaction usually requires high temperatures in order to surmount the high activation barrier of the cycloreversion. Moreover, the strategy of retro Diels±Alder reaction is used in organic synthesis to mask a diene fragment or to protect a double bond [47]. Some examples are illustrated in Scheme 1.11. The retro Diels±Alder reaction is strongly accelerated when an oxide anion substituent is incorporated at positions 1 and 2 of the six-membered ring which has to be cycloreversed, namely at one terminus carbon of the original diene or at one sp2 carbon of the dienophile [51] (Equation 1.22). 2 2 1 1 1:22 + The first example of an oxide-anion accelerated retro Diels±Alder reaction was reported by Papies and Grimme [52]. The adduct 19 (Equation 1.23) treated with tetra-n-butylammonium fluoride (TBAF) in THF at room temperature is immediately converted into 20, in contrast to the parent 21 (Equation 1.24) which undergoes cycloreversion into 22 at 100 8C. The dramatic oxide-anion acceleration (> 106 ) was ascribed to the loss of basicity of about 8 pKb units in the transformation of alcoholate ion of precursor 19 E H E E TBAF 20 ⬚C E TMSO H E E + E TMSO O n -Bu4N 19 E = CO2Me E O n -Bu4N 20 1:23 Diels±Alder Reaction: General Remarks 17 Synthesis of (+ -) -occidentalol [48] O O O 150 ⬚C + H −CO2 O O MeO2C CO2Me O O H CO2Me H OH Synthesis of (+ -) -turmerone [49] O O O CHO 1. 2. MeMgI/Cu + distillation at 78 mbar O Synthesis of 2-glycosylamino pyridines [50] O Me H N E N MeX N O R DMA, 80 ⬚C 64−89% NH E O NH Gly N N Me MeX OAc OAc AcO − MeNCO E E Gly N XMe X = O, S R = H, CH2OAc E = CO2Me Scheme 1.11 into the phenolate ion of the product 20. This is an example of acceleration of retro Diels±Alder when an oxide substituent is incorporated at the terminus of the 4p component of the Diels±Alder adduct, that is, position 2 in the model of Equation 1.22. E 100 ⬚C E + E E 21 E = CO2Me 1:24 22 An example of the effect of oxide-anion associated with the 2p component (i.e. position 1, Equation 1.22) is illustrated in Equation 1.25 [53]. The potassium salt of 1,4-dihydro-11-hydroxy-9,10-dihydro-9,10-ethanoanthracene undergoes more facile debridging (remotion of ethylene) than the 11-deoxygenated parent compound. 18 Homo-Diels±Alder Reaction OK 25 ⬚C, 18 h 69% 1:25 1.8 200 ⬚C, 18 h KF, THF, 25 ⬚C 28% 17 h, 71% HOMO-DIELS±ALDER REACTION The reaction of a diene having the two double bonds separated by a sp3 center with a dienophile to give a [2p 2p 2p] cycloaddition is called a homo-Diels±Alder reaction. Since the diene is not conjugated, a s bond is created in lieu of a double bond. In principle, an open-chain diene gives rise to a central-bridged six-membered ring, while an inner-ring diene produces a bridged six-membered ring fused with a ring whose size depends on the size of the starting cyclodiene (Equations 1.26 and 1.27). Norbornadienes are the dienes most often used to investigate the homo-Diels±Alder reaction. + 1:26 + 1:27 A minority of authors use the term homo not to indicate the relative position of the two double bonds of diene involved in the reaction, but to emphasize that the six-membered adduct is formed by all carbons [54]. The cycloaddition between norbornadiene (23 in Scheme 1.12) and maleic anhydride was the first example of a homo-Diels±Alder reaction [55]. Other venerable examples are reported in Scheme 1.12 [56]. Under thermal conditions, the reaction is generally poorly diastereoselective and occurs in low yield, and therefore several research groups have studied the utility of transition metal catalysts [57]. Lautens and coworkers [57c] investigated the cycloaddition of norbornadiene and some of its monosubstituted derivatives with electron-deficient dienophiles in the presence of nickel-cyclooctadiene Ni COD2 and PPh3 . Some results are illustrated in Tables 1.4 and 1.5. The mechanism of metal-catalyzed homo-Diels±Alder reaction proposed by Noyori [57c, 58] requires the coordination of double bonds of diene and Diels±Alder Reaction: General Remarks 19 CN CN 200 ⬚C, 12% NC NC CN CN O O NC CN NC CN O Rfx, 100 % ⬚C, 205 low yield 23 H O O H O COMe COMe Scheme 1.12 dienophile to the metal followed by the formation of metallocyclobutane which is converted to metallocyclohexane and then to the cycloadduct (Scheme 1.13). Table 1.4 Ni(COD)2 /PPh3 catalyzed homo-Diels±Alder reaction of norbornadiene with electron-deficient dienophiles R + Ni(COD)2 /PPh3 + DCM R R endo exo R T(8C) COMe CHO COt-Bu CN SO2 Ph SOPh 80 20 60 80 20 20 exo/endo >20 3 1.5 4 1 7 Yield (%) 99 58 69 82 75 65 20 Multiple Diels±Alder Reaction Table 1.5 Ni COD2 =PPh3 catalyzed homo-Diels±Alder reactions of 2-carboxyethylnorbornadiene with electron-deficient dienophiles MeO2C CO2Me + R Ni(COD) /PPh 2 3 80 ⬚C, DCM CO2Me MeO2C + CO2Me + R ortho R para + R R meta' meta R ortho (exo/endo) para (exo/endo) meta (exo/endo) meta 0 (exo/endo) Yield (%) CN SO2 Ph COMe 0 0 20 (0:1) 100 (1:2.3) 66 (>20) 70 (3) 0 0 0 0 33 (>20) 10 (1:1.4) 94 75 84 R + 23 Ni(COD)2 2 PPh3 L = COD R Ni L R Ni Ni L R L L R Scheme 1.13 1.9 MULTIPLE DIELS±ALDER REACTION Processes consisting of two or more synthetic steps carried out in the same flask without isolating any intermediates have been widely investigated in the last decade due to their ecological and economic advantages when compared to a stepwise procedure. In this respect the Diels±Alder reaction is a frequent example. The one-pot multistep process has been named in various ways: domino, cascade, tandem, timed, consecutive, transmissive, etc. Sometimes the word used does not describe the real meaning of the procedure in that there is no conformity between the customary use of the term and the chemical transformation. These terms were recently defined more pertinently [59]. A domino Diels±Alder reaction (the term was chosen from the well-known game) is a one-pot process involving two or more Diels±Alder reactions carried out under the same reaction conditions without adding additional reagents or catalyst such that the second, third, etc., cycloaddition is the consequence of the functionality generated in the previous reaction. A historical example is illustrated in Equation 1.28 [60]. This type of transformation is sometimes named tandem or cascade, but these terms seem less appropriate for describing a timeresolved transformation. Diels±Alder Reaction: General Remarks 21 E E E E E + E THF − 78 ⬚C 4h 17% 1:28 E = CO2Me E E H E E H A tandem Diels±Alder reaction (the term refers to two operating units that are distinct but working at the same time) would indicate a process involving two distinct Diels±Alder reactions working at the same time (Equation 1.29) [6], and a cascade Diels±Alder reaction would refer to a transformation involving at least two Diels±Alder reactions occurring in sequence, without any reference to the fact that the subsequent reaction is the consequence of the functionality generated in the previous reaction (Equation 1.30) [61]. E + O O 80 ⬚C O 1:29 O O H E E = CO2Me O H E OSMT OSMT ∆ CCl4 Ph E OSMT 1:30 Ph Ph O O O A consecutive or timed Diels±Alder reaction is a one-pot process in which the first Diels±Alder does not promote the second, so it is necessary to change the experimental conditions or add reagents to allow the successive cycloadditions (Equations 1.31 [62] and 1.32 [63]). O O O +O O O 19 kbar 95% O 200 ⬚C −CO2 87% O O O O O 1:31 22 Theory OMe CO2Me CO2Me CO2Me 1:32 OSMT + H O Sometimes it is difficult to classify a one-pot multi-step process. Thus for the sake of clarity, we think that the more general term multiple reaction is preferable to indicate a one-pot process in which several bonds are formed sequentially, regardless of whether the reaction conditions are changed or not, or whether new reagents are added during the process. 1.10 THEORY According to frontier molecular orbital theory (FMO), the reactivity, regiochemistry and stereochemistry of the Diels±Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41±43, 64] These orbitals are the closest in energy; Scheme 1.14 illustrates the two dominant orbital interactions of a symmetryallowed Diels±Alder cycloaddition. 1.10.1 Reactivity and Substituent Effects The reactivity of a Diels±Alder reaction depends on the HOMO±LUMO energy separation of components: the lower the energy difference, the lower is the transition state energy of the reaction. Electron-withdrawing substituents lower the energy of both HOMO and LUMO, while electrondonating groups increase their energies. HOMO diene-controlled Diels± Alder reactions (Scheme 1.14) are accelerated by electron-donating substituents in the diene and by electron-withdrawing substituents in the dienophile LUMO LUMO HOMO HOMO normal inverse Scheme 1.14 Diels±Alder Reaction: General Remarks 23 (normal electron-demand Diels±Alder reaction). LUMO diene-controlled Diels±Alder reactions are influenced by electronic effects of the substituents in the opposite way (inverse electron-demand Diels±Alder reaction). The neutral electron-demand Diels±Alder reaction is HOMO±LUMO-diene controlled and is insensitive to substituents in either the diene or the dienophile. Lewis acids can greatly accelerate the cycloaddition. Instructive examples are the AlCl3 -catalyzed reaction of cycloalkenones with 1,3-butadienes [12]. The catalytic effect is explained by FMO theory considering that the coordination of the carbonyl oxygen by Lewis acid increases the electron-withdrawing effect of the carbonyl group on the carbon±carbon double bond and lowers the LUMO dienophile energy. 1.10.2 Regioselectivity The ortho±para rule is explained by FMO theory on the basis of the orbital coefficients of the atoms forming the s-bonds. The regiochemistry is determined by the overlap of the orbitals that have larger coefficients (larger lobes in Scheme 1.15). The greater the difference between the orbital coefficients of the two end atoms of diene and two atoms of dienophile, which form the two s-bonds, the more regioselective the cycloaddition. LUMO ED EW ED EW EW + HOMO EW = electron-withdrawing ED normal ED = electron-donating Scheme 1.15 Lewis-acid-catalyzed cycloadditions of dienophiles, such as a,b-unsaturated carbonyl compounds, with open-chain carbon-dienes, are generally highly ortho±para regioselective because the oxygen complexation increases the difference of LUMO coefficients of the alkene moiety. The orbital interaction depicted in Scheme 1.15 shows that the two s-bonds form at the same time but do not develop to the same extent. The Diels±Alder cycloaddition of unsymmetrical starting materials is therefore concerted but asynchronous. A highly unsymmetrical diene and/or dienophile give rise to a highly unsymmetrical transition state and a stepwise pathway can be followed. 24 Theory A concerted and synchronous Diels±Alder reaction occurs only with symmetric nonpolar reagents. 1.10.3 Stereoselectivity The FMO theory explains the kinetically favored endo approach considering an additional nonbonding interaction. This secondary orbital interaction does not give rise to a bond but contributes to lowering the energy of the endo transition state with respect to that of the exo one. The larger are the lobes of interacting orbitals, the better is the overlap, the stronger is the interaction, and the more favored is the formation of endo adduct. In the cycloaddition between piperylene and acrolein (Scheme 1.16), the secondary orbital interaction occurs between the C-2 of the diene and the carbonyl carbon of the dienophile. LUMO LUMO E O 2 1 Me HOMO E = Lewis acid O 2 1 HOMO Me Scheme 1.16 The complexation with Lewis acids or the protonation influences both the energy and the coefficients of carbon atoms of the LUMO orbital of the dienophile. The coefficient of the carbonyl carbon orbital increases (Scheme 1.16); consequently, the stabilizing effect of the secondary orbital interaction is greatly increased and the endo addition is more favored. The stereochemistry of substituents at C-1 and C-4 of the diene and that of substituents at C-1 and C-2 of the dienophile are preserved in the cycloadduct because the Diels±Alder is a concerted reaction that takes place suprafacially on both components. In a photochemical cycloaddition, one component is electronically excited as a consequence of the promotion of one electron from the HOMO to the LUMO*. The HOMO*±LUMO* of the component in the excited state interact with the HOMO±LUMO orbitals of the other component in the ground state. These interactions are bonding in [22] cycloadditions, giving an intermediate called exciplex, but are antibonding at one end in the [p 4s p 2s ] Diels± Alder reaction (Scheme 1.17); therefore this type of cycloaddition cannot be concerted and any stereospecificity can be lost. According to the Woodward± Hoffmann rules [65], a concerted Diels±Alder reaction is thermally allowed but photochemically forbidden. Diels±Alder Reaction: General Remarks 25 LUMO* LUMO HOMO* HOMO Scheme 1.17 Stable cis-1-phenyl-1-cyclohexene 24 photodimerizes via Diels±Alder cycloaddition to trans adduct 25 (Equation 1.33) [66] and the photoexcitation of dihydrobenzofuran-fused cyclohexenone 26 in net furan gives the trans fused Diels±Alder adduct 27 (Equation 1.34) [67]. 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Soc. 1995, 117, 10276. 58. Takaya H., Yamakawa M. and Noyori R. Bull. Chem. Soc. Jpn 1982, 55, 852. 59. Lombardo M. and Trombini C. Seminars in Organic Synthesis. 23rd Summer School `A. Corbella', Italian Soc. Chem., Rome, 1998, 7. 60. Paquette L., Wyvratt M., Berk H. and Moerck R. J. Am. Chem. Soc. 1978, 100, 5845. 61. Krauss G. A. and Tashner M. J. J. Am. Chem. Soc. 1980, 102, 1974. 62. (a) Swarbrick T., Marko I. and Kennard L. Tetrahedron Lett. 1991, 32, 2549; (b) Marko I., Seres P., Swarbrick T., Staton I. and Adams H. Tetrahedron Lett. 1992, 33, 5649. 63. Danishefsky S., Schuda P. F., Kitahara T. and Etheredge S. J. J. Am. Chem. Soc. 1977, 99, 6066. 64. (a) Isaacs N. Physical Organic Chemistry, 2nd edn, Longman, Harlow, 1995; (b) Fleming I. Pericyclic Reactions, Oxford Science Publ. 67, Oxford University Press, 1999. 28 References 65. Woodward R. B. and Hoffmann R. The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim, 1970. 66. Goodman J. L., Peters K. S., Misawa H. and Caldwell R. A. J. Am. Chem. Soc. 1986, 108, 6803. 67. (a) Mintas M., Schuster D. I. and Williard P. G. J. Am. Chem. Soc. 1988, 110, 2305; (b) Mintas M., Schuster D. I. and Williard P. G. Tetrahedron 1988, 44, 6001. The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 2 2.1 Thermal Diels±Alder Reaction INTRODUCTION From 1928 when Otto Diels and Kurt Alder [1] made their extraordinary discovery until 1960 when Yates and Eaton [2] reported the acceleration of the Diels± Alder cycloadditions by Lewis acid catalysts, these reactions were essentially carried out under thermal conditions owing to the simplicity of the accomplishing thermal process. Since then a variety of methods have been developed to accelerate the reactions. The reaction between 1,3-butadiene and ethylene (Equation 2.1) is a typical example of a thermal Diels±Alder cycloaddition. 200 ⬚C + 2:1 20% Since the reactivity depends on the lowest HOMO±LUMO energy separation that can be achieved by the reacting partners, all the factors, steric and electronic, that lower the HOMO±LUMO distance increase the reaction rate and, as a consequence, allow the reactions to be carried out under mild conditions. Thus the normal electron-demand Diels±Alder reaction between 1,4benzoquinone and 1,3-butadiene (Equation 2.2) proceeds at 35 8C almost quantitatively. O H PhH, 35 + O ⬚C 2:2 quantitative O H O There are many types of Diels±Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 2.2 2.2.1 CARBON DIELS±ALDER REACTIONS Open-Chain Dienes Highly functionalized cyclohexenes have been prepared by Diels±Alder reactions of butadienes 1 (Scheme 2.1) and chiral butadienes 2 (Scheme 2.2) with 30 Carbon Diels±Alder Reactions various dienophiles [3,4]. Good regio- and facial selectivities were observed with dienes 2 bearing a free hydroxy group; when this group was protected the stereoselectivity was reversed and lowered. When the chiral dienes 3, bearing E R E E PhMe, Rfx, 48 h, 73−75% R E E R E E PhMe, Rfx, 48 h, 70−88% 1 E E R E E E PhMe, Rfx, 48 h, 73−77% R = CH2CH(OAc)Ph, CH2CH(OAc)CH2CH2Ph E = CO2Me Scheme 2.1 Z R OR1 2 Z R Z + R + R OR1 PhH, Rfx, 48 h 70−92% OR1 Z OR1 + R Z OR1 Z = COMe, CO2Me, CONM2 R = i-Pr, n-C6H13, Ph, p-BrC6H4, p-MeOC6H4 R1 = H, Me, STM, TBDMS Scheme 2.2 an S-()-2-methoxymethyl pyrrolidine as chiral auxiliary, were used to react with nitroalkenes, a variety of optically active cyclohexanones [5] were obtained (Equation 2.3). The cycloadditions were highly diastereoselective, showed a high level (92±95 %) of enantiomeric excess and, after hydrolysis of the cycloadducts, furnished optically active nitrocyclohexanones. Thermal Diels±Alder Reaction 31 OR OR R1 −80 + N ⬚C NO2 THF, r.t. MeOH NO2 to r.t. R2 aq. AcOH-AcONa pH 4.6 O R1 R2 O overall yield: 32−76% 2:3 3 R = Me, OMOM, TBDMS; R1 = H, Me; R2 = H, Me, CH2OBn, i-Pr, Ph, 2-Fu, 3-Fu, o-Cl-C6H4, p-OMe-C6H4, p-NO2-C6H4; R1-R2 = −(CH2)4− Conjugated cyclohexenones [6] have also been easily prepared by combining the cycloaddition of dimethylaminobutadiene 4 and several cyclic and acyclic dienophiles followed by the elimination of the amino group from the cycloadducts under acidic conditions. Scheme 2.3 summarizes some of these results. O TBSO N Ph O O O H O N Ph O O O 1. −70 ⬚C, 96% 2. SiO2, 83% O O O 1. 80 ⬚C, 17 h 2. HF 76% Me 1. 110 ⬚C, 48 h 2. HF 60% TBSO 1. E 4 NMe2 TBSO 80 ⬚C, 25 h, 66% 1. E O O + E E E = CO2Me Scheme 2.3 E E 2. LiAlH4/HF 1. 20 ⬚C, 92% 2. HF O O 2. LiAlH4/HF 85% O O E OH OH OH OH 32 Carbon Diels±Alder Reactions This type of diene is also interesting because the amino substituents open up the possibility of using chiral amines, thus allowing optically active conjugated cyclohexenones to be synthesized. An example is the chiral aminosiloxy diene 5 which reacts with several dienophiles leading to cycloadducts that were directly converted into chiral cyclohexenones [7] (Scheme 2.4) with fairly good yield (64±82 %) and high enantiomeric excess (86±98 %). The amino functionality can also be retained [8] as shown by the Diels±Alder reactions of 2aminomethylbutadienes 6 (Equation 2.4) with a variety of dienophiles (dimethylfumarate, dimethylmaleate, methylacrylate, ethylacrylate and dimethylacetylenedicarboxylate). TBSO R2 R3 R1 CO2R + Ph N Ph TBSO PhMe, 20 ⬚C 24−72 h Ph N 5 R2 R2 O R3 R3 1. LiAlH 4 R1 OH 2. HF 10% CO2R R 1 Ph overall yield: 64−82% R = Me, Et, t-Bu; R1 = H, Et; R2, R3 = Ph, CO2Me, CO2Et Scheme 2.4 A one-pot procedure [9] based on the cycloaddition of 4-aryl-2-silyloxybutadienes 7 and bisdiene 8 with alkynes, followed by oxidative aromatization of the cycloadducts, opened a route to polycyclic phenols without isolating the cyclohexadiene derivative intermediates (Scheme 2.5). R1 R1 R CO2Me + N CO2Me CHCl3, Rfx 20 h, 50−79% R1 R1 N R CO2Me CO2Me 2:4 6 R = H, CH2NMe2; R1 = Me, Et The synthesis of halogen-containing organic substrates is currently a stimulating challenge for synthetic chemists. Among the many procedures that have been developed, Diels±Alder methodology has also been successfully used. Trichlorinated tropones [10] have been prepared by a one-pot procedure based on thermal cycloaddition of tetrachlorocyclopropene 9 with electronrich butadienes (Scheme 2.6) followed by spontaneous ring-expansion/dehydrochlorination of the resulting cycloadducts. Thermal Diels±Alder Reaction 33 TMSO TMSO 7 R R = Ph, 2-Fu, 2-Th, p-PhC6H4 R1 8 R2 1. PhMe, 100 ⬚C, 27 h 2. DDQ, AcOH-PhMe, Rfx, 20 h 19−85% 1. PhMe, 100 ⬚C, 24 h 2. DDQ, Rfx, 8−20 h 35−64% R1 HO OH R OSMT R2 R2 R1 R1 R2 OH R1, R2 = H, CN, CO2Me Scheme 2.5 O Cl OMe Cl Cl OMe CCl4, r.t., 2 d, 53% MeO OSMT Cl OSMT Cl OSMT Cl Cl 9 OMe O OAc OMe O CCl4, r.t., 4 d, 40% CCl4, r.t., 4 d, 56% OH Cl Cl Cl Cl Cl Cl Scheme 2.6 Aromatic fluoro-compounds have been prepared by thermal cycloaddition of fluorinated 1,3-butadienes 10±12 (Figure 2.1) with several dienophiles. Fluorophenols were obtained by cycloaddition of diene 10 with quinones [11] 34 Carbon Diels±Alder Reactions F OSiPh3 F CF3 R2 R OSMT F R1 11 10 12 R, R1, R2 = H, Me, OMe, OSMT Figure 2.1 (Scheme 2.7). The phenols were formed during isolation (chromatography on silica gel) from the corresponding cycloadducts. In the reaction with p-benzoquinone, a product was unexpectedly obtained from a hetero-Diels± Alder reaction with the quinone acting as a carbonyl dienophile. The Diels±Alder reactions of dienes 11 and 12 with many dienophiles allowed other fluorinated aromatics to be synthesized [12,13]. For example, diene 11 reacted with dimethylacetylenedicarboxylate and ethylpropiolate (Scheme 2.8) to give trifluoromethyl diethylphthalate and trifluoromethylethylbenzoate, and diene 12 with p-benzoquinone affords 5-fluoronaphthoquinone (Equation 2.5). Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels±Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. O OH O F Ph3SiO F 1. PhH, 110 ⬚C, 20 h, 45% 2. SiO2 HO F OH OH 10 1. PhH, 90 ⬚C, 10 h, 69% O 2. SiO2 + Ph3SiO HO F O Scheme 2.7 O OH O F F Thermal Diels±Alder Reaction 35 F3C E E E 100 ⬚C, 18 h, 63% E F3C E = CO2Me CF3 OSMT CO2Et/I2 H 11 100 ⬚C, 72 h, 28% CO2Et Scheme 2.8 O H O O PhMe, 25 ⬚C, 15 h + 65% F OSMT HCl, 91% F TMSO O H 2:5 F O O 12 R O O R1 R Ot-Bu + R2 PhH, ∆, 3.5-5 h 57−100% O R R2 DDQ CO2t-Bu R2 Ot-Bu O OH R1 N R3 O O R1 −H2O R3NH2, DCM, 42−72% 42−90% R, R1, R2 = H, Me, CH2CO2Et; R3 = n-Bu, Bn Scheme 2.9 Diels±Alder cycloaddition reactions are among the most common and expeditious methods for the derivatization of [60]-fullerene which acts as a good dienophile reacting with a wide variety of dienes bearing electron-donating and electron-withdrawing groups. Since cycloadducts undergo a facile retroDiels±Alder reaction, the stability of the cycloadducts was attained either by incorporating the forming double bond into an aromatic ring or by a smooth conversion of the formed double bond into a single bond. 36 Carbon Diels±Alder Reactions Diels±Alder reactions of butadienes 13 and 2,3-di-n-propylbutadiene 14 with [60]-fullerene 15 led to several fullerene derivatives [15±17] (Scheme 2.10). Dienes 13 and 14 bore electron-donating groups, but the reactions also occurred with electron-withdrawing substituents due to the sufficiently lowenergy LUMO of C60 . TMSO R R R R1 C60 O THF HCl C60 R1 R1 13 C60 PhMe, 50−110 ⬚C OSMT 0.5−24 h, 29−48% 15 14 PhH, Rfx, 14 h, 54% C60 R = R1 = H, Me, OMe, Ph Scheme 2.10 Vinylboranes, a class of highly reactive dienophiles that has been explored by Singleton and coworkers [18±21], have been used to synthesize a wide variety of cyclohexenols, cyclohexenediols and bridgehead bicyclic alcohols by Diels± Alder reaction with a wide range of acyclic dienes. The alcohols are obtained by an oxidative H2 O2 /NaOH work-up of the intermediate borane adducts; by adding triethylamine before proceeding with oxidation, the protodeboronation side- reaction was eliminated and alcohols were obtained in good to excellent yields. Vinylborane can be readily prepared by metal±metal exchange of boron halides with vinyltin derivatives. While 9-vinyl-borabicyclo [3.3.1]nonane (18) is unstable and was therefore generated in situ and trapped by dienes, the trans1,2-bis(catecholboryl)ethylene (19) is an air-stable crystalline solid [19]. The cycloadditions of numerous vinylboranes have been studied and some significant examples are summarized in Equations 2.6 and 2.7 and Scheme 2.11. Generally, the cycloaddition reactions have shown high regioselectivity and endo-diastereoselectivity. SnBu3 + 16 Br-9-BBN DCM, r.t. t -Bu DCM, r.t., 20 h B 5 min BBN t -Bu 17 2:6 18 OH t -Bu 82% overall yield H2O2 NaOH Thermal Diels±Alder Reaction 37 O B SnBu3 neat, 25 ⬚C O + Br B B 3 d, 70% O Bu3Sn O O O 19 2:7 OH t -Bu H2O2 t -Bu Et3N, 100 ⬚C, 1h NaOH OH 70% yield SnBu3 ( )n BBr3, hexane 0−25 ⬚C, 15 min BBr2 ( )n HO hexane, 25 ⬚C Et3N, NaOH H R1 R 41−80% R R, R1, R2 = H, Me, Ph, t-Bu, R1 ( )n H2O2 R2 n = 1, 2 R2 H2C Scheme 2.11 2.2.2 Cyclopentadienes and Cyclohexadienes Cyclopentadienes and cyclohexadienes are versatile dienes that are commonly used to study mechanistic, regio- and stereochemical aspects of the Diels±Alder reaction and for synthetic purposes. Cycloaddition reactions of homochiral dihydropyranones 20, readily accessible from d -glucose, with cyclopentadiene 21 give optically active tetrahydrobenzopyranones bearing several stereogenic centers. The reactions of these poorly reactive dienophiles were carried out under drastic thermal, Lewis-acid catalyzed, high pressure conditions [22]. Although mixtures of four diastereoisomers (endo/exo and syn/anti) were always obtained, the highest yields and stereoselection were observed under thermal (Equation 2.8) and, especially, high pressure conditions (15 kbar, 25 8C, 2 d). Norbornadienes, norbornenones and their homologs have been prepared [23, 24] by cycloaddition of cyclopentadiene (21) and cyclohexadiene (22) with 1-benzenesulfonyl-2-trimethylsilylacetylene (23) and 1-ethoxy-2-carbomethoxyacetylene (24). Both were efficient dienophiles in the cycloaddition processes and dienophile 23 acted as an effective acetylene equivalent (Scheme 2.12). Norbornanes and their homologs can also be attained by Diels±Alder reaction 38 Carbon Diels±Alder Reactions of dienes 21, 22 and fulvene 25 with acetoxymaleic anhydride (26), a reactive dienophile, which behaves like a ketene equivalent [25] (Scheme 2.13). OBz OBz OBz H DCM, 150−250 ⬚C O + R1 BzO O R1 2-6 d, 76−92% R BzO O 20 21 H O + R R1 BzO O R 2:8 O R = R1 = H, OMe, OBz The cycloaddition between 25 and 26 is a crucial step for the synthesis of methyl cis-dihydrojasmonate, a key constituent of the commercial jasmine fragrance Hedione 27. MeO2C OEt ( )n 24 45−80 ⬚C, 24 h 21, n = 1 22, n = 2 ( )n PhO2S SiMe3 23 MeOH or PhH, 0−60 ⬚C 2−8 h, 96−100% ( )n OEt SiMe3 CO2Me SO2Ph THF, HCl 3h LiAlH4 THF, 92−94% ( )n O F , THF 7−8 h, 76−100% 43−65% overall yield ( )n CO2Me ( )n O Scheme 2.12 Optically active norbornene derivatives [26] have been prepared by cycloaddition of hexachlorocyclopentadiene with l-menthylacrylate and l-menthylallylether (Equation 2.9). Low levels of enantiomeric excess have been obtained in the thermal processes, whereas Lewis acid catalyzed reactions (BF3 , BBr3 , AlCl3 , SnCl4 , DCM, 40±80 8C) gave better results. Thermal Diels±Alder Reaction OAc O O O O AcO 22 PhH, 110 ⬚C, 24 h, 4−7% 39 OAc 21 PhH, 25 ⬚C, 24 h, 82% O O 26 O O O O 13 h/50 ⬚C and 19 h/80 ⬚C 25 OAc O + O O OAc O O O CO2Me O 27 Scheme 2.13 Cl Cl CO2-l-menthyl Cl 160 ⬚C, 8 h, 65% Cl Cl Cl Cl Cl Cl 1. OH 2. H Cl Cl CO2-l-menthyl Cl CO2H 2R-(−) Cl Cl Cl 2:9 Cl Cl Cl Cl Cl CH2O-l-menthyl Cl 160 ⬚C, 8 h, 83% Cl Cl Cl Cl Cl Cl H Cl CH2O-l-menthyl Cl Cl CH2OH 2R-(−) 40 Carbon Diels±Alder Reactions Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(l-menthyloxy)-2-(5H)-furanone (28) underwent Diels±Alder reaction with cyclopentadiene (21) with complete p-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. H R*O O PhMe, 110 ⬚C, 65% + O O H H OR* 21 28 O 2:10 R* = l-menthyl Very high levels of diastereomeric and enantiomeric excess have been observed in the cycloadditions of (5R) and (5S)-5-menthyloxy-2(5H)-furanones 28 and 29 (Figure 2.2), readily available from furfural and d- and lmenthol [28]. R*O R O O 28 R*O 29 O O R* = l-menthyl Figure 2.2 2.2.3 Heterocyclic Dienes The reactivity of heterocyclic dienes is determined by the nature and number of heteroatoms and, in the case of heteroaromatic compounds, also by the aromatic character. Furans undergo Diels±Alder reactions with strong dienophiles and generally afford exo-cycloadducts which are thermodynamically more stable than the kinetically favoured endo-adducts. An example of the Diels±Alder reaction of furans is the cycloaddition of 31 with 4,4-diethoxybut-2-ynal (32) which acts as an acetylenedicarbaldehyde synthon to afford 7-oxabicyclo [2.2.1]heptene derivatives [29] which were then converted into substituted cyclohex-1-ene-1,6-dicarbaldehydes by a four-step procedure (Scheme 2.14). Thiophenes are less reactive than furans and therefore react with very reactive dienophiles. They behave somewhat differently from furans and in many cases the intermediate addition products are unstable and undergo cheleotropic extrusion of sulfur [30]. Thiophenes 30 undergo cycloaddition reactions with DMAD (Equation 2.11) to afford bicyclic cycloadducts which lead to phthalates by sulfur extrusion, thus offering a one-pot synthesis of dimethylphthalates [31]. Thermal Diels±Alder Reaction 41 CHO O R O + CHO 5−20 h, 100% CH(OEt)2 31 R Na2CO3, BHT, 70 ⬚C CH(OEt)2 32 CH(OEt)2 TBDMSO H2, Pd/C EtOAc 100% CH(OEt)2 CHO HO KOt-Bu, TMEDA R CHO −55−23 ⬚C, 80−90% TBDMSCl imidazole 80% R O CHO R CH(OEt)2 CHO SiO2/(CO2H)2 TBDMSO CHO DCM, 90−95% R R = Me, Et, Bu, n -C5H11, n -C7H15, n -C8H17 Scheme 2.14 Benzo[c]furans (isobenzofurans) are very reactive but generally unstable dienes which are prepared in situ and trapped. The in situ-generated isobenzofuran 33 was trapped by cycloaddition reaction with bis(methyl (S)-lactyl) ester 34 to afford [32] optically active naphthols (Equation 2.12). The cycloaddition was carried out in the presence of a catalytic amount of glacial acetic acid and represents a facile one-pot procedure to synthesize substituted naphthols. R1 xylene, Rfx + R S R2 CO2Me R2 2−96 h, 16−75% CO2Me 30 R1 R CO2Me 2:11 CO2Me R, R1, R2 = H, Me, OMe, SMe, Ph Because of their low reactivity, a Diels±Alder reaction of 2-pyrones usually requires such a high temperature that the initial bicyclic lactone adducts often undergo cycloreversion [30,33] with loss of CO2 . In some cases this limitation has been overcome by carrying out the reaction under high pressure conditions. Posner and coworkers have shown [34 ±36] that the presence of a tolylthio group or a bromine atom at the 3- or 5-position increases the reactivity of 2-pyrones. 3-Bromo-2-pyrone (35) (Scheme 2.15), as well as its regioisomer 5-bromo (36) 42 Carbon Diels±Alder Reactions OH CO2R* MeO DCM, AcOH, 95 O + Et3B MeO CO2R* MeO CO2R* Ar Ar 2:12 33 34 R* = LiAl(t-BuO)3H 40 min, 80% MeO CO2R* ⬚C Me H CO2Me Ar = 3,4-(MeO)2C6H3 (Equation 2.13), undergo slow but very clean regioselective cycloaddition reactions, under carefully controlled thermal conditions with both electron-poor and electron-rich dienophiles. O Br O R O CHO Br O O O O R = H, Me DCM, 78−90 ⬚C 33−63% R O DCM, 90 ⬚C, 63% H O O Br O DCM, 90 ⬚C 63% O O 35 OMe OMe DCM, 80 60% ⬚C Br O O O O O Br OMe OMe O Scheme 2.15 O R O + 25−100 ⬚C, 2−5 d 83−100% Br O R O Br 36 R = CN, COMe, CO2H, OCH2CH2Cl, OSiMePh2, p-Br-C6H4 2:13 Thermal Diels±Alder Reaction 2.2.4 43 Outer-Ring Dienes Outer-ring dienes are very reactive and readily form Diels±Alder adducts with olefinic and acetylenic dienophiles. Several types of outer-ring dienes are based on their nature (carbodiene or heterodiene) and ring type (carbocyclic or heterocyclic). Their reactivity is related to the distance between the methylene carbons and is strongly influenced by the presence of heteroatoms in the ring and substituents in the diene moiety. Many routes for generating these dienes from precursors have been studied; when generated in the presence of a dienophile, they give the adducts directly [30]. Various o-quinodimethanes, generated in situ from o-alkenylbenzyltributylstannane precursors, have been used to synthesize functionalized polycycles by Diels±Alder reaction with maleic anhydride, methylacrylate, dimethylfumarate and N-phenyl maleimide in the presence of electrophiles [37] (Scheme 2.16). H R3 ArS R1 ArS R3 R2 ArSCl R3 H R R1 DCM, r.t., 2 h, 51−95% R R2 SnBu3 O R-R1= O C O C , R2 = H; R = CO2Me, R1 = R2 = H O Ph O R1 = R2 = CO2Me, R = H; R-R1 = C N C , R2 = H Ar = Ph, o -NO2C6H4; R3 = H, Me, Ph, CO2Et Scheme 2.16 2,3-Dimethylene-2,3-dihydrothiophene (37, Figure 2.3) is the thiophene analog [38] of o-quinodimethanes and has been used to develop a Diels±Alderbased synthetic approach to benzothiophene derivatives. Generated in situ by treating the trimethylsylyl ammonium derivatives 38 or 39 with Bu4 N F , it X Z Figure 2.3 S S 37 38 39 X = Me3N+I−; Z = SiMe3 X = SiMe3; Z = MeEt2N+I− 44 Carbon Diels±Alder Reactions has been trapped with a variety of dienophiles (dimethyl maleate and fumarate, acrylonitrile, methylacrylate, diethylazodicarboxylate). The fluoride-induced 1,4-elimination procedure [39] allows 37 to be generated under mild conditions; this is of particular importance due to the strong tendency of diene 37 to dimerize or polymerize. For example, the reaction of diene 37 with N-phenyl maleimide is described in Equation 2.14. O N Ph O NMe3I SiMe3 Bu4NF O S S MeCN, 20 ⬚C 89% S O 37 38 2:14 N Ph Pyrano-[4,2-b]-pyrrol-5-ones (40) and pyrano-[4,3-b]-pyrrol-6-ones (41) (Figure 2.4) are stable cyclic analogs of pyrrole 2,3-quinodimethane and undergo Diels±Alder reaction [40, 41] with various dienophiles to afford indole derivatives after loss of carbon dioxide. R R O O N R1 O 40 O N SO2Ph 41 R = H, Me; R1 = CO2i -Bu Figure 2.4 Scheme 2.17 reports some cycloaddition reactions of pyrano-[4,3-b]-pyrrole 40 (R Me, R1 CO2 -i-Bu). Tamariz and coworkers [42] have described a versatile, efficient methodology for preparing N-substituted-4,5-dimethylene-2-oxazolidinones 42 (Figure 2.5) from a-diketones and isocyanates and have also studied their reactivity in Diels±Alder reactions. This is a method for synthesizing polycyclic heterocyclic compounds. Some of the reactions of diene 42 are summarized in Scheme 2.18. The nitrogen atom seems to control the regiochemistry of the reaction. 2,3-Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). Thermal Diels±Alder Reaction 45 MeO2C N CO2i-Bu MeO2C DMAD PhCl, Rfx, 18 h, 88% SOPh O MeCN,PhCl, ∆, N O 6 h, 84% CO2i -Bu PhCl, Rfx N 144 h, 85% CO2i-Bu N CO2i-Bu 40 CO2Et H PhCl, Rfx 20 h, 75% EtO2C + N CO2i-Bu EtO2C N CO2i-Bu Scheme 2.17 O R N O R1 42 R = (CH2)2Cl, Ph, p-ClC6H4, m-ClC6H4, o-MeC6H4, m-MeC6H4, p-MeC6H4, o-BrC6H4 R1 = H, Me Figure 2.5 Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels±Alder reactions of the dienes 44 are reported in Scheme 2.19. The Diels±Alder reaction provides a valuable tool for functionalizing buckminsterfullerene (C60 ). Functionalized C60 derivatives may have important applications as conductive materials [45] and in biological chemistry [46]. 46 Carbon Diels±Alder Reactions R1 O CO2Me N R CO2Me O CO2Me R1 180 ⬚C, 1 h 56−85% CO2Me O O R1 CO2Me N O N O R H + CO2Me R N O xylene, 60−130 ⬚C 18 h, 0−40% R1 R1 O O xylene, 130−160 ⬚C 1 h, 63−90% 42 O N R R + R1 O O N R R1 = H, Me; R = Ph CO2Me COMe O COMe O 180 ⬚C, 1 h 75−79% N Ph O R1 O H O O N Ph N R H O Scheme 2.18 o-Quinodimethanes and their heterocyclic analogs have been used to functionalize (C60 ) fullerene by cycloaddition reactions affording thermally stabilized cycloadducts. Thieno-o-quinodimethanes 46 and 48, generated in situ by iodide-induced 1,4-elimination from the respective 2,3-bis(chloromethyl)thiophene 45 and 2,3-bis(bromomethyl)benzo[b]thiophene 47 precursors, undergo Diels±Alder R1 S + R S O O O O O O S DCM or PhH, 60−160 ⬚C 2−180 h, 26−97% R1 S O R 2:15 O 43 O Ph O R = OEt, SPh, TMS, OAc, CO2Me, COMe, Ph; R1 = H; R-R1 = −(CH2)4−, C N C Thermal Diels±Alder Reaction 47 O O O N Ph H N O H N , X=H O H PhBr, ∆, 5 h, 58% X Ph O N H ∆ O O O,X=H O H N X PhBr, ∆, 2.5 h, 45% N H 44 CO2Me MeO2C CO2Me , X = CO2Me CO2Me PhBr, ∆, 26 h, 54% N CO2Me Scheme 2.19 reaction with fullerene (15) in the presence of 18-crown-6 ether, yielding (Equations 2.16 and 2.17) thiophene-containing monocycloadducts [47]. C60 Cl Cl MeO2C PhMe, NaI, 18-crown-6 Rfx, 3 d, 23% S MeO2C 15 C60 S S C60 Br Br 47 2:16 46 45 S CO2Me PhMe, NaI, Rfx 18-crown-6, 24 h, 43% C60 15 S 2:17 S 48 Bis-o-quinodimethanes have also been used to functionalize [60]-fullerene by Diels±Alder reaction. An example is the preparation of main-chain polymers with incorporated [60]-fullerene units [48] illustrated in Scheme 2.20. Cycloaddition of bis-diene 50 generated in situ from bis-sulfone 49 with [60]-fullerene leads to an oligomer mixture 51. Another type of functionalization is based on the 48 Carbon Diels±Alder Reactions OHex OHex O2S SO2 ∆ OHex OHex 49 50 C60 15 Cl3C6H3, Rfx, 20 h OHex OHex C60 C60 OHex C60 n OHex n = 0−5 Hex = C6H11 51 Scheme 2.20 Diels±Alder reaction of fullerenes with complex dienes type 52 (Figure 2.6) which have a 2,3-bis-(methylene) bicyclo[2.2.2]octane unit [49]. H H H H 52 OMe O AcHN OMe Figure 2.6 H2N O Thermal Diels±Alder Reaction 2.2.5 49 Inner-Outer-Ring Dienes Inner-outer-ring dienes are very useful in the synthesis of polycyclic molecules. Their reactivity in the Diels±Alder reaction depends on the type of ring (carbocyclic, heterocyclic, aromatic) that bears the ethenyl group or on the electronic effects of substituents at the diene moiety [30]. The 3- and 6-acetoxyvinylcyclohexenes 53 and 54 react with dimethylacetylenedicarboxylate to afford bicyclic esters [50]. It is noteworthy that the facial diastereoselectivity depends on the position of the acetoxy group (Scheme 2.21). While the reaction of 53 is completely anti-diastereoselective, that of 54 is undiastereoselective, affording a 1:1 mixture of cycloadducts. E 30% E 6 5 AcO 4 3 3 PhMe, Rfx + 53 16−40 h E E 42% AcO 6 53, 3-OAc 54, 6-OAc E H OAc E = CO2Me H E E + AcO 6 H E Scheme 2.21 The cycloadditions of the C-2 vinyl glicals with maleic anhydride are an interesting example of facial stereocontrol. The allylic methoxy group in dienes 55a and 55b exerts an anti-stereodirecting effect as shown by the stereochemistry of the endo-cycloadducts 56 and 57 obtained as the sole products from 55a and 55b, respectively, and by the fact that 55c produces [51] a mixture of the diastereoisomers 56c and 57c (Scheme 2.22). When linear acetylenic dienophiles were used, the degree of facial diastereoselectivity decreased, which indicates its dependence on steric effects. Styrenes and vinylnaphthalenes Styrenes may act as 2p and 4p components of the Diels±Alder reaction depending on the substitution site and the electronic effects of the substituent. Electron-donating groups at the a-carbon of the olefinic double bond enhance the dienic reactivity of styrenes [30]. 50 Carbon Diels±Alder Reactions H O O O + Ph O H R O R1 O 55 O H O Ph O O H H O H O O H O H R O H H O H O H R R1 57 Ph R1 56 O a, R = OMe, R1 = H b, R = R1 = OMe c, R = R1 = H Scheme 2.22 Phenanthrene-1,4-diones have been prepared [52] by cycloaddition of asubstituted styrenes with an excess of 1,4-benzoquinone (Equation 2.18). Initial cycloadducts are oxidized by 1,4-benzoquinone. R O O R PhMe, Rfx + 2:18 15−20 h, 31−57% O O R = H, OMe, SMe, Me(CH2)3O(CH2)2O In contrast, product mixtures were obtained [53] when a-substituted styrenes were reacted with dimethylacetylenedicarboxylate (Equation 2.19). The products were formed via aromatization of the primary cycloadducts or by `ene' addition of a second molecule of DMAD. E E E R R E PhH or PhMe + E 100−200 ⬚C 20−24 h, 30−88% R = OMe, OEt, OSiMe3; E = CO2Me E R E + + E E E 2:19 E E Thermal Diels±Alder Reaction 51 When strong electron-withdrawing substituents were introduced at the aor b-carbon of the vinyl group, the styrenes acted as dienophiles. Thus cycloaddition of a-trifluoromethyl styrene (58) with Danishefsky's diene 59 afforded regioselectively a 1:1 mixture of cycloadducts which were then converted (Equation 2.20) into 4-phenyl-4-trifluoromethyl-2-cyclohexen-1-one [54]. O OSMT F3C OMe THF, 140 ⬚C, 140 h, 75% + or 15 kbar, 80% OSMT 58 OMe CF3 H3O 80% CF3 2:20 59 Similarly, b-nitrostyrene (60) reacted with 1-dimethylamino-1-alkylbutadienes to afford phenylnitrocyclohexenes [55] (Equation 2.21) regioselectively and stereoselectively. NO2 NMe2 + R H PhMe, Rfx 8 h, 26−71% NO2 R 2:21 NMe2 60 R = Me, Et, i -Pr, n-Pr, n-Bu 1-Vinylnaphthalenes give Diels±Alder reactions more easily than styrenes and have been used to synthesize steroid-like compounds. 2-Vinylnaphthalene (61) is less reactive than 1-vinylnaphthalene (62) (Figure 2.7); it requires drastic conditions to undergo Diels±Alder reaction and the yields are low. Better results can be obtained by carrying out the reaction under high pressure (Chapter 5). Some Diels±Alder reactions of 1-vinylnaphthalene (62) are summarized in Scheme 2.23. 61 Figure 2.7 62 52 Carbon Diels±Alder Reactions O H O R O CN CO2Me [56] CO2Me CN CN O CO2Me O CN R MeO2C O [57] [56a] (CN)2=(CN)2 O 62 O H O O OAc [58] [58] H O H [59] O O O H O H H O Scheme 2.23 Divinylnaphthalenes 63 and 64 (Figure 2.8) react with strong dienophiles and have been used to synthesize complex polycyclic aromatic compounds [60]. While 2-vinylnaphthalene (61) and 1-vinylnaphthalene (62) act as 4 components, 3-vinylphenanthrene (65) and 1- vinylpyrene (66) (Figure 2.8), characterized by an extended polycyclic aromatic system, preferentially undergo [22] cycloaddition [57, 61, 62]. RO 63 Figure 2.8 OR 64 65 66 Thermal Diels±Alder Reaction 53 3,4-Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphthalene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67± 69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-1one, which is a precursor of inden-1-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 67 O [63] H H H H + H H H O 3 H + H O 1 2 DDQ, PhH, Rfx, 15 h 61% O + O 2 1 Scheme 2.24 O 54 Carbon Diels±Alder Reactions O O + CCl4, Rfx, 75% O 68 H O H triglyme, Rfx, 60 h Pd/C [65] H major Scheme 2.25 O MeO O O [65] H O H OMe MeO O [66] H O O 69 O OMe [66] [67] O H [66] MeO O MeO O O O O H MeO H + O O O O MeO Scheme 2.26 O Thermal Diels±Alder Reaction 55 Dihydrovinylphenanthrenes Dihydrovinylphenanthrenes are more reactive than the corresponding vinyl phenanthrenes and undergo Diels±Alder reactions easily. They have been used in the synthesis of polycyclic aromatic compounds and helicenes. Examples of cycloaddition reactions of the 3,4-dihydro-1-vinylphenanthrene (70), [61] 3,4-dihydro-2-vinylphenanthrene (71) [68] and 1,2-dihydro-4vinylphenanthrene (72) [69] are reported in Equation 2.22 and Schemes 2.27 and 2.28. O O 1. Et3N, Rfx, 6 h, 43% + + 2. Pd/C, 53% 2:22 O Br 70 In the case of the cycloaddition of 71 with benzyne (Scheme 2.27) a 1.5:1 mixture of the two products was obtained which were then oxidized to the O O H H RH , DME 1. 2. DDQ R CCl4, Rfx, 48 h, 50% R1 71 i) NaBH4 DCM/MeOH, ⬚ ii) Pd/C 160 C, 24 h 53% overall yield: 42% R1 = H, Ph R R = H, OMe Scheme 2.27 56 Carbon Diels±Alder Reactions O 1. O O O 1. PhMe, Rfx, 20 h 2. DDQ, PhH, Rfx, 5 h , DME 2. DDQ, PhH, Rfx, 16 h 72 overall yield: 30% overall yield: 37% Scheme 2.28 corresponding aromatic compounds. The major component was the product of the cycloaddition which originated the minor product by ene-reaction with a second molecule of dienophile. The Diels±Alder reactions of 71 with 2-inden-1-ones generated in situ by treating the corresponding 3-bromo-indan-1-ones with triethylamine, were highly regio- and stereoselective; the cycloadducts were easily dehydrogenated to afford helicenes. Diene 72 underwent cycloaddition reactions with p-benzoquinone and benzyne to give cycloadducts which were dehydrogenated to [5]phenacenes. Vinylfurans, vinylthiophenes and vinylpyrroles 2-Vinylfuran (73a) and 2-vinylthiophene (73b) (Figure 2.9), and more generally 2-vinyl- and 3-vinyl five-membered aromatic heterocycles and their benzoderivatives, may undergo Diels±Alder reaction in two different ways by involving either the aromatic nucleus (intra-annular addition) or the diene moiety including the side-chain double bond (extra-annular addition). The latter way of interacting is preferred [30] and involves mechanistic and theoretical aspects, allowing substituted condensed heterocyclic systems to be synthesized [70]. Y X X X 73 a, X = O b, X = S Y OSMT Y 74, X = O 75, X = S Y Figure 2.9 Y Y : dienophile Thermal Diels±Alder Reaction 57 Whereas furan is more reactive than thiophene, according to the different aromatic character [71], the corresponding vinyltrimethylsilyloxy derivatives 74 and 75 show an opposite order of reactivity [72]. The reversed reactivity has been explained in terms of FMO theory by considering the higher energy of the HOMO (diene) and the larger HOMO coefficient at the end of the silyloxyvinyl group in the thiophene derivative 75 compared with that in the analogous furan 74. This shows that the reactivity of vinylheterocycles is not simply related to their aromaticity. The Diels±Alder reaction of 2-vinylfurans 73 with suitable dienophiles has been used to prepare tetrahydrobenzofurans [73, 74] by an extra-annular addition; these are useful precursors of substituted benzofurans (Scheme 2.29). In practice, the cycloadditions with acetylenic dienophiles give fully aromatic benzofurans directly, because the intermediate cycloadducts autoxidize during the reaction or in the isolation procedure. In the case of a reaction with nitrosubstituted vinylbenzofuran, the formation of the aromatic products involves the loss of HNO2 . DDQ R 73% O R R O R2 CN CN E E O R2 R1 R1 E R O R = R1 = H R2 = CO2Et R2 R1 85% DDQ R R2 R = R1 = H, R2 = CO2Et R1 R R2 O R = R1 = H, R2 = NO2 E , 140 ⬚C, 40 h, 53% R = R1 = H, R2 = NO2 R1 73 E R O R1 E E xylene, Rfx, 24 h, 40% R1 = R2 = H R =p -NO2C6H4 E R = R 1 = R2 = H 140 ⬚C, 18 h, 62% E , 140 ⬚C, 48 h, 57% O 140 ⬚C, 40 h 73% CN CN R2 R1 CN PhH, 80 ˚C, 24 h, 5% E E E E R R O O R2 R1 E = CO2Me Scheme 2.29 R2 R1 58 Carbon Diels±Alder Reactions There is marked competition between intra-annulation and extra-annular addition in the case of 3-vinylfuran as shown by the results of the cycloaddition of 76 with several dienophiles [75] (Scheme 2.30). OSMDBT OSMDBT CO2Me + O CO2Me O CO2Me MeO2C CO2Me CO2Me CO2Me PhMe, r.t. 72 h, 45% OSMDBT CO2Me O MeO2C CO2Me CO2Me + OSMDBT CO2Me OH TBDMSO CO2Me , PhMe O Rfx, 56 h, 39% CO2Me O CO2Me MeO2C O CO2Me O PhMe, 5 d, 45% O O 76 MeO2C O SOPh CO2Me PhMe, r.t, 5 h, 67% OSMDBT O H O MeO2C S Ph Scheme 2.30 2-Vinyl- and 3-vinylthiophene (73b and 77) are less reactive than the corresponding furans and show a notable preference for extra-annular addition due to the higher reactivity of the diene system, including the side-chain double bond. 2-Vinylthiophene is less reactive than 3-vinylthiophene. Whereas 2vinylthiophene (73b) reacted with maleic anhydride and 1,4-benzoquinone to give cycloadducts in reasonable yield, 3-vinylthiophene (77) gave a higher yield of the cycloadduct [76, 77] (Scheme 2.31). Vinylpyrazoles fail to undergo cycloaddition reactions under conditions used for vinylfurans and vinylthiophenes. 1-Phenyl-4-vinylpyrazole (78) and 1phenyl-5-vinylpyrazole (79) (Figure 2.10) react only with strong dienophiles under pressure and at high temperatures [78±80]. Thermal Diels±Alder Reaction O O 59 O O PhH, Rfx, 50% O AcOH, 43% S 73b O O O O O S S O 80% O + S S O O 77 Scheme 2.31 N N N N Ph Ph 78 79 Figure 2.10 Vinylbenzofurans, vinylbenzothiophenes and vinylindoles These dienes are valuable for the Diels±Alder based synthesis of dibenzofurans, dibenzothiophenes, carbazoles and other classes of complex polycyclic heterocyclic compounds. Scheme 2.32 summarizes some of the cycloadditions [81] of 2-vinylbenzofurans (80). Substituted dibenzofurans have also been obtained by cycloaddition of 3vinylbenzofurans (81) as shown [82] in Scheme 2.33. 60 Carbon Diels±Alder Reactions MeO2C O O R O O MP, PhMe, Rfx, 7 d, 12% R BQ, PhMe, Rfx, 48 h, 32% OMe MA, PhH Rfx, 24−60 h 80−82% O O O O 80 R R = H, Me DMAD, PhH or xylene Rfx, 5−72 h 25−33% TCNE, CHCl3 r.t., 12−24 h 90% MeO2C O O R CO2Me R CN NC CN CN MeO O R MP = methylpropiolate; BQ = 1,4-benzoquinone; MA = maleic anhydride; DMAD = dimethylacetylenedicarboxylate; TCNE = tetracyanoethylene Scheme 2.32 As vinylbenzofurans allow a large variety of substituted dibenzofurans to be synthesized, 2- and 3-vinylbenzo[b]thiophenes allow an easy entry, by Diels±Alder reaction with the appropriate dienophiles, to substituted dibenzothiophenes which are not easily accessible by other methods. Vinylbenzo[b]thiophenes are less reactive than the corresponding vinylbenzo[b]furans. Some cycloaddition reactions of 2-vinylbenzo[b]thiophene (82) with various dienophiles are reported [83] in Scheme 2.34. The Diels±Alder cycloadditions of both 2-vinylindoles and 3-vinylindoles are very attractive methods for preparing [b]annelated indoles to serve as lead substances and as building blocks for alkaloids. Pindur and coworkers [84] have extensively studied the vinylindole Diels±Alder chemistry. Cycloaddition reactions of 2-vinylindoles 83 with a variety of dienophiles provide a convenient access [85] to carbazoles (Scheme 2.35). Thermal Diels±Alder Reaction 61 R2 H O X H O R 1O X = O, N-Ph MA or NPM, PhH, r.t. 3 h, 60−80% R2 R2 H O O TCNE, PhH, r.t. NQ,n-PrOH R1 r.t., 44% H R1 O R2 O 81 0.5−1 h, 50−83% CN CN CN O R1 CN R1 = R2 = H, Me MA = maleic anhydride; NPM = N-phenylmaleimide; NQ = 1,4-naphthoquinone; TCNE = tetracyanoethylene Scheme 2.33 O O S BQ, AcOH,100 ⬚C 8 h, 51% O O NC NQ, n-PrOH S CNCN CN TCNE, THF, r.t., 44% 0−25 ⬚C, 21 h,66% S 82 COPh PhH, Rfx, 8 h, 54% COPh PhOC COPh S BQ = 1,4-benzoquinone; NQ = 1,4-naphthoquinone; TCNE = tetracyanoethylene Scheme 2.34 S 62 Carbon Diels±Alder Reactions X Z X H R1 PhMe, MS 4A, Rfx, 7−40 h, 12−73% R N H R1 Z E E H E PhMe, Rfx, 3−16 h, 20−46% R N H E R1 R N H 83 R = H, Me; R1 = H, Me, Ph [1,3]-H shift [1,3]-H shift Z X − H2 R1 N H X-Z = O Ph O N E E R R1 ; X = H, Z = CO2Me N H E = CO2Me X = H, Z = CO2Et; X = Z = CO2Me R Scheme 2.35 The reactivity and regioselectivity of the cycloadditions of the 2-vinylindoles are markedly dependent on the substitution pattern as shown by the calculated HOMO energies and coefficients [85a]. In the case of the reaction of 2-vinylindole (83, R R1 H) with methyl propynoate, a diester is obtained by a multiple one-pot process involving two molecules of the dienophile and the extrusion of ethene (Equation 2.23). CO2Me CO2Me H CO2Me N H N H CO2Me N H 2:23 H CO2Me PhMe, MS 4A Rfx, 5 d, 8% N H MeO2C CO2Me N H − CH2=CH2 CO2Me 3-Vinylindoles have been studied extensively and used in the synthesis of carbazoles, alkaloids and other classes of pharmacologically active compounds. MMX force field calculations have shown that coplanar s-cis and strans conformations of 3-vinylindole (84, Figure 2.11) are the most stable conformers; they exhibit only slight differences in their thermodynamic stabilities [86]. Thermal Diels±Alder Reaction 63 N N 84 Figure 2.11 Preparation of 3-vinylindole (84) via Cope elimination of N,N-diethyltryptamine-N-oxide has been reported [87]. An alternate approach based on the Wittig reaction of the readily accessible N-phenylsulfonylindole-3-carbaldehyde failed because cleavage of the sulfonyl protecting group easily produced an anion whose neutralization led to polymerization [86]. Noland and coworkers have developed an interesting methodology for the in situ synthesis of carbazoles. This methodology combines the synthesis of 3vinylindoles from indoles and acyclic ketones with the subsequent Diels±Alder cycloaddition in one flask to produce a variety of tetrahydrocarbazoles [88] (Scheme 2.36). R2 R1 R1 CO2H CO2H acetone, Rfx 82−99% N N N HCl Acetone CO2H + R1 R2 r.t., 84−96% R2 H R1 O O + R2 O H O O 90−120 ⬚C, 3−18 h 12−67% O N O R2 H R1 R2 H R1 N O O H H O N R1 = Me, Et, Ph, CH2COMe, p- and m-XC6H4 (X = Me, OMe, Br, Cl, F, NO, Ph) R2 = H, Me, Et, Bn, Me3CCOCH2 Scheme 2.36 64 Carbon Diels±Alder Reactions Enantiomerically pure tetrahydrocarbazoles have been obtained by asymmetric Diels±Alder reactions [89] of 2- vinyl- and 3-vinylindoles with Oppolzer's acryloylsultam. The results of the [42] cycloadditions of 3-vinylindoles (Scheme 2.37) show that the exo-addition is preferred. R* + N R1 R2 R2 R2 DCM, MS4A 18−120 h, 20−40 ⬚C 2−24% O N H R1 O + R* N SO2 R* endo exo R* = N H R1 O R1 R2 PhSO2 Me Me Me Me Me Ph exo/endo > 99:< 1 74:26 > 99:< 1 > 99:< 1 N Scheme 2.37 2.2.6 Across-Ring Dienes 3,30 ,4,40 -Tetrahydro-1,10 -binaphthalene (bisdialine) (85) is more reactive than the corresponding 1,10 -binaphthalene and has been used as a 4 component of cycloadditions to prepare very complex molecules. An improved method for preparing 85 was recently described [90]. The Diels±Alder reactions of 85 with a number of dienophiles were studied [90, 91] and are illustrated in Scheme 2.38. Thermal Diels±Alder Reaction 65 O O N Ph O O BQ excess, 150 ⬚C, 22 h 25% DDQ,triglyme, Rfx, 18 h 25% O H NPM, 150 ⬚C NQ 50% 3 h, 40% H H O N Ph H O O 85 MA NO2C6H5, 87% O O BQ = 1,4-benzoquinone; NPM = N-phenylmaleimide; NQ = 1,4-naphthoquinone; MA = maleic anhydride Scheme 2.38 Tetramethylbisdialine 86 has been used to synthesize substituted pentahelicenes characterized by a relatively high energy barrier to racemization due to the marked steric interactions between the methyl groups at the terminal aromatic rings [68b] (Scheme 2.39). 66 Hetero-Diels±Alder Reactions , DME 1. 2. triglyme, Rfx, Pd/C, 30% O O 1. excess O , 150 ⬚C, 4.5 h 2. triglyme, Rfx, Pd/C, 30% O O 86 O 1. excess O , PhMe, Rfx, 18 h 2. triglyme, Rfx, Pd/C, 26% O Scheme 2.39 2.3 HETERO-DIELS±ALDER REACTIONS The hetero-Diels±Alder reaction permits heterocyclic-six- membered rings to be constructed by the interaction of heterodienes and/or heterodienophiles. Both the intermolecular and intramolecular versions of the hetero-Diels±Alder reaction are, therefore, very important methods for synthesizing heterocyclic compounds. 2.3.1 Heterodienes Diels±Alder reactions of 1-azadienes are less thermodynamically favorable [92] than the all-carbon analogs because of the stronger carbon±nitrogen -bond which is broken during the Diels±Alder reaction. Reactivity of 1-azadienes 87 and the regioselectivity and stereoselectivity of the cycloadditions with dienophiles 88 are strongly dependent on the type of Thermal Diels±Alder Reaction 67 substituent at the nitrogen atom and on the nature of the dienophile. While azadiene 87a was the most reactive, 87c did not react and only the polymerization of the dienophile was observed [92] (Equation 2.24). Ph Ph R1 r.t., −120 ⬚C + NC Ph N + 1−8 d, 40−92% R1 NC R N R1 NC N R 87 2:24 R 88 R1 = Ph, EtO, CO2Me a, R = CO2Et b, R = Ph c, R = OMe 1-Azadienes 89, generated in situ by thermolysis of the corresponding oaminobenzylalcohols, have been used for the derivatization of [60]-fullerene through C±N bond formation leading to tetrahydropyrido [60]-fullerenes [93]. Theoretical calculations predicted these cycloadditions to be HOMO azadienecontrolled (Equation 2.25). R R OH C60 R Rfx C60 DCB NH 2:25 N N 89 R = Ph, 2-Th, p-MeOC6H4 Thioazadienes 90, formed in situ by the reaction of trimethylsilylimines and isothiocyanates, underwent cycloaddition reactions with nitriles bearing electron-withdrawing groups, to afford 1,3,5-thiadiazines [94] in excellent yield (Equation 2.26). R N R1 N R + S R2CN 1. PhMe, 25 ⬚C, 6−24 h 2. H2O, 80−91% HN R1N SiMe3 90 R = Ph, 2-Th; R1 = Ph, p -ClC6H4; R2 = Ts, CCl3, CO2Me N S R2 2:26 68 Hetero-Diels±Alder Reactions a, a0 -Dioxothiones are another type of heterodienes that contain two heteroatoms. They are electron-poor dienes which are readily formed in situ and are then trapped by electron-rich alkenes. Cycloadditions of thiones 91 and 92 (Scheme 2.40) are regiospecific and chemospecific [95]. S O R1 O R1 S O Py, CHCl3, r.t., 24 h, O 85% , R1 = Me O O R1 S O S Py, CHCl3, r.t., 63−64 h, 79−89% O O O S O Py, CHCl3, r.t., 20−23 h, 88−97% S O O R1 R1 Py, CHCl3, r.t., O 2.5−17 h, 67−78% 91, R1 = Me O 92, R1 = OMe O S Scheme 2.40 o-Thioquinones 93, prepared simply from o-hydroxythiophthalimides, behave like a,a0 -dioxothiones, affording a variety of complex heterocyclic compounds by inverse electron-demand Diels±Alder reaction [96] (Equation 2.27) with both vinyl ethers and electron-rich alkenes. R R R1 O R2 S O + R3 Py, CHCl3, r.t. 5−50 h, 58−87% R1 O O S R2 R3 2:27 93 R = OH, OMe; R1 = Me, OMe; R-R1 = −(CH=CH)2−; R2-R3 = (CH=CH)2−; R-R1 and R2-R3 = −(CH=CH)2− Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels±Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). Thermal Diels±Alder Reaction 69 R R-X -Bu3SnX CHCl3 or PhMe, −60-110 ⬚C, 0.2−48 h 39−86% SnBu3 N Ph N N + CO2Me Ph CO2Me N 95 SnBu3 SnBu3 1. [4 + 2] + 2. − N 2 Ph CO2Me Ph N 94 N 72% CO2Me 10% Br S RX = HCl, Cl2, Br2, I2, PhI, N Br , N N, X Br , PhCOCl, COCl (X = O, S) Scheme 2.41 The combination of thionation by Lawesson's reagent [98] of oxoenaminoketones 96 with normal electron-demand Diels±Alder reaction of conjugated aldehydes allows a variety of thiopyrans 97 to be synthesized by a regioselective and chemoselective one-pot methodology [99] (Equation 2.28). Thionation occurred at the more electrophilic ketonic carbonyl group. O O CHO CHNMe2 + EtO O Lawesson's reagent PhH, 0 ⬚C-r.t., 56−63% R CHO EtO S 96 R = H, Ph 2:28 R 97 The thionation±cycloaddition sequence is accompanied by the elimination of dimethylamine from the cycloadduct to afford thiopyrans. Similarly, when the thionation±cycloaddition methodology was applied to enaminoketones 98 and 99, obtained from thiochromanones, tricyclic compounds 100 and 101 were obtained (Figure 2.12). CHO R CHNMe2 O S 98 Figure 2.12 O S 99 CHNMe2 S S S 100 R = H, Me, Ph S 101 CHO 70 Hetero-Diels±Alder Reactions A Diels±Alder reaction of arynes with 1,2,4-triazines 102 allows the preparation of isoquinolines substituted with electron-withdrawing groups in the nitrogen-containing ring. The isoquinoline-1-carboxylic esters bearing additional substituents are of particular interest because they are not readily available by the usual routes [100,101] (Scheme 2.42). R2 R1 N CO2Et 1,4-dioxane, Rfx, 0.5 h 27−77% R2 R2 R1 R1 R2 N + N CO2Et R2 R1 N R1 1,4-dioxane, Rfx, 0.5 h, 30−69% N + N 1,4-dioxane, Rfx, 0.5 h, 20−69% CO2Et 102 R2 R1 N N CO2Et CO2Et CO2Et R1, R2 = H, Me, Ph, CO2Et Scheme 2.42 2.3.2 Heterodienophiles Silylthioaldehydes 103, reactive dienophiles formed in situ from acetals according to a general method, are directly trapped with dienes to afford sulfur-containing heterocyclic compounds in good yield (Equation 2.29). Silylthioaldehydes are quite reactive in comparison with the aliphatic ones [102] which are rather inert in the cycloaddition reactions. R1 R1 O O H SiR MeCN, r.t., HMOST CoCl2 . 6H2O, 24 h, 37−64% S H SiR 103 R = Me3, Et3, t-BuMe2, PhMe2, Ph2Me R1 = Me, R1-R1 = −(CH2)3− S H SiR 2:29 Thermal Diels±Alder Reaction 71 Selenoaldehydes 104, like thioaldehydes, have also been generated in situ from acetals and then directly trapped with dienes, thus offering a useful onepot procedure for preparing cyclic seleno-compounds [103,104]. The construction of a carbon±selenium double bond was achieved by reacting acetal derivatives with dimethylaluminum selenide (Equation 2.30). Cycloadditions of seleno aldehydes occur even at 0 8C. In these reactions, however, the carbon± selenium bond formed by the nucleophilic attack of the electronegative selenium atom in 105 to the aluminum-coordinated acetal carbon, may require a high reaction temperature [103]. The cycloaddition with cyclopentadiene preferentially gave the kinetically favorable endo isomer. Se R1 R1 O O + (Me2Al)2Se H R PhMe-Dioxane, 25−100 Se ⬚C H 3 h, 18−96% R R Se 105 2:30 104 R R = Me, i-Pr, C7H15, Ph, Bn R1 = Me, Et Selenoaldehydes have also been obtained by reacting chlorocarbonyl compounds with selenide ions generated by a fluorodestannylation technique using Bu3 Sn2 Se and Bu4 NF3H2 O [105]. Selenoaldehydes 104 bearing an electronwithdrawing group such as CO2 Me, COMe, COPh or CN were efficiently prepared and trapped by dienes, whereas when R was Ph or MeO groups, selenoaldehydes were not generated (Scheme 2.43). Se RCHCl2 + (Bu3Sn)2Se + 2 Bu4NF.3H2O H R 104 Se R R1 R2 R1 Se + Se R R R2 major endo:exo = 80:20 − 14:86 THF, r.t. 3 h, 70−79% R2 R1, R2 = H, Me Se , R = CO2Me Se THF, r.t., 3 h, 22−71% H R THF, r.t., 3 h, 24% R1 R 104 endo:exo = 80:20 R = CO2Me, COMe, PhCO, CN Scheme 2.43 72 Hetero-Diels±Alder Reactions A carbon±selenium bond can also be formed [106] by Diels±Alder reaction of the transient selenonitroso species 106 generated by phenylsulfinylselenylchloride reacting with amines or trimethylsilylated amines. Selenonitroso compounds 106 were trapped with 2,3-dimethylbutadiene to afford 1,2-selenazine derivatives 107 (Scheme 2.44) in low yield. 1,2- Selenazines are interesting compounds which are quite unstable (2±3 h), except for the one having an H R PhSO2SeCl, Et3N, DCM R N R1 [R-N=Se] 0 ⬚C, 0-20% N Se 106 107 R = p-XC6H4 (X = Br, Me), o -SMeC6H4, PhO(CH2)2 R1 = H, SMT N S Se Scheme 2.44 ortho-thiophenyl-substituent which presumably increases the stability (3 days) by virtue of a nonbonded five-membered ring S Se interaction [107]. Diels±Alder reaction of tosylimine 108 obtained by thermal [22] cycloaddition of p-toluensulphonylisocyanate and methylglioxylate [108] provides a method for synthesizing nitrogen-containing heterocycles. The tosylimine was not isolated but was used directly in situ in several cycloaddition reactions (Scheme 2.45) which were completely regioselective [109]. In the case CO2Me CHO TsN=C=O + PhMe, Rfx 36 h R1 R1 R N Ts R 0-70 ⬚C, 3-24 h, CO2Me 50-83% ( )n , n = 1, 2 TsN=CHCO2Me 108 R 0 ⬚C, r.t., 24 h, 57-70% O R, R1 = H, Me, OMe, OSMT R = H, Me R O NHTs CO2Me Scheme 2.45 ( )n CO2Me NH Ts Thermal Diels±Alder Reaction 73 of furan and 2-methyl furan, only electrophilic aromatic substitution at the aposition was observed. The cycloaddition of chiral, racemic and non-racemic alkoxybutadienes 109 with phenyltriazolinedione led to aza compounds [110] in high yield, with good facial selectivity (diastereomeric excess: 87±92 %) (Equation 2.31). The cycloadditions of the same dienes with N-phenylmaleimide require Lewis acid catalysis. R1 N O OR* N R1 + N N Ph O THF, -100 ⬚C to r.t. N Ph N R*O O + R1 12 h, 87-91% O 109 N R*O R1 = n-Pr, Ph, 2-Fu, trans-2-phenylcyclohexyl R* = trans-2-phenylcyclohexyl 2:31 O N Ph N O Chiral heterocyclic compounds containing vicinal oxygen and nitrogen atoms were achieved by an asymmetric Diels±Alder reaction [111] of chiral acylnitroso dienophiles 111. The latter were prepared in situ from alcohols 110, both antipodes of which are available from camphor, and trapped with dienes (Scheme 2.46). Both the yield (65±94 %) and diastereoisomeric excess (91±96 %) were high. R* OH 110 R*OCONHOH R* = camphor chiral auxiliary O N R*O ( )n n = 1, 2 O 111 DCM −78 ⬚C to r.t., 3 h R1 R1 = Me, CO2Et O O ( )n R*O R*O N R1 N O O 65−94% 89−93% Scheme 2.46 74 2.4 Hetero-Diels±Alder Reactions INTRAMOLECULAR DIELS±ALDER REACTION A Diels±Alder reaction can also take place intramolecularly when a molecule incorporates both the diene and dienophile moieties which are connected by a chain. Nowadays the intramolecular Diels±Alder reaction is a valuable tool in organic synthesis because it allows two rings, of which only one is formed by the [42] cycloaddition, and up to four new chiral centers to be formed in one step [112]. Both carbocyclic and heterocyclic rings may be generated depending on the nature of the interacting moieties; the size of the second ring depends on chain broadening. Wulff and Powers [113] developed a methodology for preparing bicyclic esters by intramolecular cycloaddition reactions of (E,E) and (Z,E)-deca2,7,9-trienyl (112a and 113a) and undeca-2,9,11-trienyl (112b and 113b) pentacarbonyltungsten and tetracarbonyltriphenylphosphinetungsten carbene complexes as ester synthons. Some of the results are summarized in Schemes 2.47 and 2.48. The reactions of (E,E)- compounds are highly endo-diastereoselective and the observed diastereoselectivity was far superior to that afforded by thermal cycloadditions of the corresponding organic esters. Facile oxidation of the resulting complexes using cerium(IV) occurred with the retention of the stereochemistry to afford the corresponding esters. Feringa-butenolide 114, in the presence of Dess±Martin periodinane reagent and 2,6-lutidine, gave the bis-ketone 115 which underwent intramolecular cycloaddition to afford endo-selectively the desired decalin-based lactone 116 (Equation 2.32) [114]. Double activation of butenolidic double bond strongly increases the reactivity of dienophile 115. X X MeO OMe X H PhH, or neat, 80−150 ⬚C H endo 112 a, n = 1; b, n = 2 X W(CO)5 O W(CO)4PPh 112 a b a b a b Scheme 2.47 H ( )n + 6−72 h, 15−88% ( )n OMe endo:exo 98:2 93:7 60:40 51:49 94:6 88:12 ( )n H exo Thermal Diels±Alder Reaction 75 X X OMe X OMe H OMe PhH, or neat, 40−180 ⬚C ( )n + 5−48 h, 75−97% ( )n H ( )n H H endo exo 113 a, n = 1; b, n = 2 X W(CO)5 endo:exo 45:55 78:22 35:65 49:51 113 a b a b O Scheme 2.48 An intramolecular cycloaddition reaction of 117 is the crucial step in the synthesis of the highly functionalized decalin [115] moiety of azadirachtin 119. O(+)menthyl O O O O O O OH Dess-Martin periodinane O(+)menthyl H OSPDBT O(+)menthyl OSPDBT DCM, lutidine r.t., 12 h, 79% O O OSPDBT 115 114 2:32 H 116 Cycloaddition occurred by heating compound 117 at 200 8C in a sealed tube. This led to products 118, both of which may be versatile intermediates for the total synthesis of 119 (Equation 2.33). O O O O CO2Et O O O O O O O CO2Et + H O O O 118a 117 O O H BHT, 33% O CO2Et O PhMe, 200 ⬚C, 60 h O O O O O O CO2Me OH O O OH AcO MeO2C OH H O 119 O 118b 2:33 76 Hetero-Diels±Alder Reactions ( )n ( )n R PhO2S SO2Ph R R = H, Me; n = 1, 2 120a 120b Figure 2.13 The extensive study of Craig and coworkers [116] on the intramolecular Diels±Alder reactions of E- and Z-sulphonyl-substituted deca-, undeca- and dodecatrienes 120 (Figure 2.13) has opened a short route to trans- and cisbridgehead hydrindanes and decalines and has given new insights into the role of dienophile substitution and geometry in determining the stereochemical outcome of these intramolecular cycloadditions. Decalin unit 121, an intermediate in the total synthesis of compactin, has been prepared by intramolecular cycloaddition reaction [117] of trienone-carboxylic acid 122 carried out under either thermal conditions or microwave irradiation. The desired exo-adduct 123 was the major stereoisomer (Equation 2.34). Similar results were observed in the cycloadditions of the corresponding esters. O CO2H O O H O O O H 2:34 CO2H 52% 122 123 121 Trienone 124 underwent intramolecular cycloaddition affording hydrobenzosuberone 125. Thermal reaction was poorly diastereoselective (62:38 cis:trans stereoisomers). When the cycloaddition was carried out in the presence of LiBF4 , trienone 124 was converted into cis-adduct 125 quantitatively and stereoselectively [118] (Equation 2.35). O H O PhH H 124 125 Cat. LiBF4 T ( ⬚C) 155 25 t (h) Yield (%) 5 90 72 100 cis/trans 62:38 100:0 2:35 Thermal Diels±Alder Reaction 77 Furanodecalins can be readily obtained by intramolecular cycloadditions of 2furylnonadienoates 126, 127, and 3-furylnonadienoates 128, 129. These vinylfurans reacted intramolecularly and selectively across the diene unit which includes the vinylsubstituents. Thermolysis [119] of (E,E) and (Z,E) 2-furylesters 126 and 127 gave a mixture of cis- and trans-bridgehead furanodecalins with a slight preference for the trans-isomers, and cis-furanodecalin alone, respectively (Scheme 2.49). As expected the stereochemistry of the dienoates 126 and 127 controlled the stereochemistry of the ring junction. Thermolysis of (Z,E)-3-furyl 128 and (E,E)-3-furyl 129 dienoates afforded cis-furanodecalins with a different regiochemistry of the ester functionality. The cis-furanodecalin ring system is characteristic of naturally occurring sesquiterpenes [120]. MeO2C MeO2C R1 280−290 ⬚C 63−90% O MeO2C R H H R + O O H H 126 R, R1 = H, Me MeO2C MeO2C H 280 ⬚C 100% O O H 127 H 290 ⬚C O 97% MeO2C O MeO2C H 128 H 280 ⬚C O 83% CO2Me H + O MeO2C 129 H MeO2C 40% Scheme 2.49 O H 60% 78 Hetero-Diels±Alder Reactions ( )-Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels±Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction OTBDPS O O O O OTBDPS Me Me3SiO O O O O +O PhMe, 120 ⬚C O OMOM 132 20 h, BHT, 65−70% OTBDPS t-Bu 131 Me3SiO OMOM O O 130 CO2H Me Me Me3SiO O RO O 133 O O Me OMOM (-)-chlorothricolide Scheme 2.50 OMOM Thermal Diels±Alder Reaction 79 between 130 and 131 gave two main products, the desired 132 and 133; the latter was recycled further to give 132. A sequence of two thermal intramolecular cycloadditions has been used to develop a short synthetic approach to tetrahydrothiopyrans [122]. The multiple process includes an intra-hetero- and an intramolecular-carbon Diels±Alder reaction. An intramolecular hetero-Diels±Alder reaction of divinylthioketone 134 afforded a 9:1 mixture of cycloadducts 135 and 136 which then underwent a second intramolecular cycloaddition which syn(to H-2)-exodiastereoselectively led to hexacyclic tetrahydrothiopyrans 137 and 138, respectively (Scheme 2.51). O O O O S LR, PhH, H 1 2 S H 80 ⬚C, 1 h, 94% O O O O 135 (1,2-trans) 136 (1,2-cis) 134 O O H S 1 2 HH H xylene, 140 ⬚C, 7-14 h H O O 137 (1,2-trans) (54%) 138 (1,2-cis) (81%) LR = Lawesson's Reagent Scheme 2.51 Double intramolecular hetero-Diels±Alder reaction of 1,3-diynil-bisa,b-unsaturated hydrazones 139 and 140 is a good example of a thermal multiple Diels±Alder reaction and is a particularly attractive route to annelated pyridines [123]. The initial cycloadduct readily aromatizes by the loss of dimethylamine (Scheme 2.52) under thermal reaction conditions. 80 Hetero-Diels±Alder Reactions R N N X R N X X N xylene, Rfx 17−87% N N X 139 R R = H, Me X = O, NBz N N N xylene, Rfx N 75% N N 140 Scheme 2.52 There is another type of multiple thermal Diels±Alder reaction in which the initial monoadduct is involved, either directly or after one transformation, in a second cycloaddition that affords the final polycyclic compounds. These methodologies have been used especially in the synthesis of polycyclic cage compounds. Paquette was the first to report the conversion of 9,10-dihydrofulvalene into polyfused cyclopentanoid systems [124]. Tetraene 141 has been converted into various complex polycondensed adducts by reacting with a variety of dienophiles such as maleic anhydride, N-phenylmaleimide, N-phenyltriazolinedione, p-benzoquinone and tetracyanoethylene carried out under thermal conditions. All cycloadditions occurred facial-diastereoselectively from an outside attack and provided monocycloadducts which had an exceptionally close relationship between diene and dienophile and then underwent intramolecular cycloaddition [125]. The reaction between 141 and p-benzoquinone is illustrated in Scheme 2.53. O PhMe, 100 ⬚C 24 h, 79% + O O O O 141 Scheme 2.53 O Thermal Diels±Alder Reaction 81 The synthesis of polycyclic diene 145 is another good example of this methodology [126]. Structurally, polycyclic cage compound 145 embeds the carbon skeleton of secohexaprismane [127] and iceane [128] and may serve as a synthetic precursor of these two-ring systems (Scheme 2.54). Treating the known bisdienone 142 with maleic anhydride in toluene at reflux temperature leads to cycloadduct 143 as a result of thermal decarbonylation followed by cycloaddition with the diene generated in situ. Decarbonylation of 143, followed by a second intramolecular Diels±Alder reaction, furnished caged hexacyclic ene anhydride 144 which was then converted into compound 145 by treating it with Cu2 O in hot quinoline in the presence of 2,20 -bipyridine and a small amount of water. O O O O O , PhMe H H O O O Rfx, 2 d, 68% 143 142 O DMF, Rfx, 6 h, 85% Cu2O,quinoline, H2O, Rfx, 16 h + 24 h 60% O O 144 145 O Scheme 2.54 A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl4,6-dihydrofuro[3,4-b]-furan-3-carboxylates 146 and 147. The results give further evidence of the potential of intramolecular Diels±Alder based multiple processes [129]. 2-Substituted furans and thiophenes 148 and 149, heated in the presence of 3,6-di(pyridin-20 -yl)-s-tetrazine, underwent intramolecular and intermolecular cycloadditions. The cycloadducts underwent double cycloreversion reactions with the loss of a nitrogen and dipyridyldiazine as illustrated in Scheme 2.55. The electron-deficient dipyridyltetrazine reacts with the isolated, electron-rich olefinic bond rather than with the bond conjugated with the methylcarboxylate. In addition to the multiple processes involving two Diels±Alder reactions in intra±intra, inter±intra or inter±inter molecular sequences, other processes have 82 Hetero-Diels±Alder Reactions O N N E N Py O N E N E Py Py X Py O N - N2 X X Py E Py X O + 148, X = O 149, X = S N PhMe, Rfx, 15 h N N 78-89% N Py E N N X O 146, X = O 147, X = S Py 1. OH 2. H E = CO2Me DDQ X=S S O DDQ X O X=O Scheme 2.55 been developed, including one Diels±Alder reaction in sequence with another reaction. This thus increases the synthetic potential of the thermal intramolecular Diels±Alder methodology. A significant example is the recently described procedure for synthesizing bicyclic heterocycles which is based [130±132] on the transetherification-intramolecular hetero-Diels±Alder reaction. It is a onepot procedure (Scheme 2.56) in which activated a, b-unsaturated carbonyl R O MeO R 2 R3 OH R1 150 + o-Cl2C6H4 or PhMe or xylene Rfx, 6−72 h R R2 O R1 R3 O 151 152 63−90% R = H, CN, COMe R1 = H, Me, CO2Me R2, R3 = H, Me R2 O H R3 R1 O H 153 Scheme 2.56 R Thermal Diels±Alder Reaction 83 compounds 150 interact with d,e-unsaturated alcohols 151 under thermal conditions giving the intermediate 152 which affords stereoselectively hydropyranopyran derivatives 153 in good yields. 2.5 OUTLINED DIELS±ALDER REACTIONS First asymmetric Diels±Alder reactions in the vinylhetarene series: cycloaddition with vinylindoles to enantiomerically pure carbazole derivatives [133] R2 R2 R* + N R1 DCM, MS 4A 20−40 ⬚C, 18−20 h, 2−27% R* N H R1 O O SO2 N R1 = PhSO2, Me; R2 = Ph, Me 6 dienes: 3-vinylindoles and 2-vinylindoles R* = H Face-selective and endo-selective cycloaddition with enantiomerically pure cyclopentadienes [134] R O R DCM or PhMe, r.t. X + 4−5 h, 64−100% O O (S) H O H X (both enantiomers R and S) X = O, NH; R = Ph, p-MeOC6H4, o-MeOC6H4, 2,4-(MeO)2C6H3, 2-Naphthyl Hetero-Diels±Alder reactions of 3,5-di-tert-butyl-o-benzoquinone with acyclic dienes: novel synthesis of 1,4-benzodioxanes [135] t-Bu O + O t-Bu AcO 4 dienes PhMe, 120 ⬚C, 30 h t-Bu O 90% O t-Bu H H OAc 84 Outlined Diels±Alder reactions Synthesis of functionalized aryloxy 1,3-butadienes and their transformation to dienyl ethers via Diels±Alder cycloaddition reactions [136] R2 R1 R2 E PhMe, Rfx, 20 h + R R1 E R E E DDQ R = Me, OMe, OTMS; R1 = OPh, p-MeC6H4; R2 = SBu, OSMT E = CO2Me R1 E R E overall yield: 40-92% 5 dienes, 3 acetylenic dienophiles Highly thermally stable Diels±Alder adducts of [60]-fullerene with 2-cycloalkenones and their acetals [137] O C60 ( )n xylene, Rfx, 36 h N2, 71−82% ( )n ( )n ( )n OCH2CH2OH O TsOH O C60 CHCl3−MeOH O O C60 n = 1, 2 Diels±Alder reactions of 1-(phenylseleno)-2-( p-toluensulphonyl)ethyne: a novel dienophile and ketene equivalent [138] Ts PhMe, 60 ⬚C, 6 h + Ts 90% SePh 7 acyclic and cyclic dienes SePh O Thermal Diels±Alder Reaction 85 Generation of a selenoaldehyde, a selenoketone, and telluroaldehydes by [3,3] sigmatropic rearrangement of allyl alkenyl selenides and tellurides [139] R X R R1 ∆ R X R1 R2 R2 X Et2O or PhH 130−140 ⬚C, 6−7 h 30−93% R2 R1 R = H, Me; R1 = H, Ph; R2 = Ph, CO2Me, 4-CF3C6H4; X = Se, Te An efficient synthesis of reduced flavones via Diels±Alder addition to 4H-pyran-4-ones [140] t-BuO2C O R R t-BuO2C + O PhMe, 110 ⬚C, 6 h O TMSO Ar 16−54% TMSO H O Ar R = H, OMe; Ar = Ph, p-MeOC6H4 Preparation of N-alkylketene-N-butadienyl-N,O-silyl acetals [141] OSMDBT N O R COCl + THF, −78 ⬚C R N MeOH, r.t. O 20-50% R = Me, Ph, p-MeOC6H4 Diels±Alder reaction of the dihydropyridinones V: approach to the Ircinal B core [142] OMe PhO2S + N O R H p-cymene, 200 ⬚C DCM, CSA 8−96 h 1h OSMT PhO2S N O R 53−74% R = CO2Me, (CH2)3-CN O 86 Outlined Diels±Alder reactions Synthesis of polysubstituted anilines using the Diels±Alder reaction of methyl-5aminofuroate [143] CO2Me R NH2 PhH, Rfx BF3, 1 h 74−99% R1 = H O H2N MeO2C O R CO2Me + R1 12 h, 68−99% NH2 R O N R1 R1 R NH2 R = H, Me, CO2Me R1 = CN, COMe, CO2Me, SO2Ph R-R1 = OH CO2Me PhH, Rfx R1 = H O THF, TsOH 25 ⬚C, 0.5 h 74−84% CO2Me MeO2C Ph OH BF3 R R OH O Preparation and Diels±Alder cycloaddition of 2-acyloxyacroleins. Facile synthesis of functionalized taxol A-ring synthons [144] O DCM, 120 ⬚C + Ph O O 6 dienes; 4 acyloxyacroleins O 22 h, 68% O O 2.6 + H Ph O O H O 1 Ph Thermal Diels±Alder Reaction 87 New Diels±Alder reactions of 3-vinylindoles with an aryne: selective access to functionalized [a]anellated carbazoles [145] CO2Me CO2Me THF, 40 ⬚C + 24% N Me N Me 4 vinylindoles; 2 arynes Exohedral functionalization of [60]-fullerene by 4 2 cycloadditions. Diels±Alder reactions of [60]-fullerene with electron-rich 2,3-dioxysubstituted-1,3-butadienes [146] O C60 + O O PhMe, 25 ⬚C MCPBA C60 12 h, 73% O C60 O O O H or SiO2 O C60 O O Studies of diastereoselectivity in Diels±Alder reactions of (S)S-4a,5,8,8a-tetrahydro5,8-methane-2-(p-tolysulfinyl)-1,4-naphthoquinones with cyclopentadiene [147] H H H H + H R O O DCM ⬚C, 0.5−48 h −40 to 20 75−93% O O H + R R1 R R1 EtOAc, Rfx 24 h, 75−82% R1 R = R1 = H, (S)S-SOTol O O H H H O O H + O O 88 Outlined Diels±Alder reactions Aminodienylesters. I: the cycloaddition reactions of tert-aminodienylester with a,bunsaturated carbonyl compounds, styrenes and quinones [148] NMe2 CO2Me CO2Me CO2Me MeO2C + CO2Me R xylene, r.t. or Rfx, 0.5−28 h, 10−95% R = CO2Me, CN 16 dienophiles Diels±Alder reactions of 1,3-cyclohexadienes and 3-(trimethylsilyl)propynoates. A new synthesis of ortho-(trimethylsilyl)benzoate esters [149] R SMT CO2Et PhH, 235−240 ⬚C + R R CO2Et + 14−24 h, 74−92% CO2Et SMT SMT R = H, OMe First stereoselective 4 2 cycloaddition reactions of 3-cyanochromone derivatives with electron-rich dienes: an approach to the ABC tricyclic frame of arysugacin [150] R R O R CN + PhMe, 300 ⬚C, 7 d O O R = Br O + 32% O O CN CN H R = H, Me, Cl, Br; 5 dienes 86 14 Synthesis and Diels±Alder reactions of a,b-unsaturated g-sultone [151] O O S O + PhMe, 150 ⬚C, 18 h 96% H H SO2 O 7 dienes H Thermal Diels±Alder Reaction 89 Synthesis and reactions of reduced flavones [152] R + R PhMe, 110 ⬚C, 6 h O R1 R1 O 53% TMSO TMSO R2 O H O R2 R = H, OMe; R1 = CO2Bn, CO2t-Bu; R2 = Ph, p-MeOC6H4 Furans act as dienophiles in facile Diels±Alder reactions with masked o-benzoquinones [153] R4 MeO OMe O O + R4 MeOH, 50 ⬚C R6 0.5−3 h, 36−80% R3 R1 R5 DAIB MeOH R6 R5 R 1 R2 R2 O OMe OMe R3 O 5 furans R4, R5, R6 = H, Me, CO2Me R4-R5 = -CH=CH-CH=CH- OMe OH R3 R1 R2 R1 = H, CO2Me, COMe; R2 = H, CO2Me; R3 = H, OMe Oxasilacyclopentanes as intermediates for silicon tethered ene cyclizations [154] O Si H O HOH2C Si H Si PhH, 170 ⬚C H 1.5 Li + O Si THF HOH2C Si H 1 overall yield: 67% 90 Outlined Diels±Alder reactions Stereoselective construction of tetrasubstituted exocyclic alkenes from the 4 2 cycloaddition of vinylallenes [155] R R NC CN PhMe, 25−110 ⬚C CN 0.5−5 d, 28−96% + NC R1 R1 R2 R = H, S R2 S R CN ; R1 = Me, n-Bu, SiMe3; R2 = H, Me, n-Pn, NC CN CN + R2 CN R1 NC CN CN MOMO 3 dienophiles; 5 vinylallenes 2-Bromoethylvinylarylsulfones as versatile dienophiles: a formal synthesis of epibatidine [156] + SO2 Br PhMe, 90 ⬚C, 24 h Ts 94% Br 6 dienes Anomalous products from the thermal Diels±Alder reaction of a (E)-2-thiophenylbutadiene tethered to 3-methallylcyclohexenone [157] O SPh H H PhS H Cl2C6H4, 180 ⬚C, 18 h i-Pr2EtN O H + H SPh H 53% O + H O 15% H H SPh 21% Dihydropyrones as dienophiles in the Diels±Alder reaction: application to the synthesis of 1-oxadecalones [158] O OMe O R PhMe, 25−110 + O OSBT R = CN, COMe, CO2Et, SO2Ph 6 dienes R ⬚C 20−48 h, 38−85% O H O Thermal Diels±Alder Reaction 91 A highly efficient multicomponent synthesis of pyridones and pyrimidones by a 2 2 2 strategy [159] R1 R1 Z TBMDSO PhH or CHCl3 + OR3 N O Rfx, 1−18 h, 0−72% H CO2Me Z N CO2Me R2 R2 R1 = H, Me, Bu, Ph, F, Cl; R2 = H, Me; R3 = TBDMS, i -Pr, Et; Z = H, Me, CO2Me 9 dienes, 8 dienophiles Synthesis of 3,5-disubstituted pyridazines by regioselective 4 2 cycloadditions with ethynyltributyltin and subsequent replacement of the organotin substituent [160] SnBu3 N N N N Ar + DCM, r.t. or MeCN, 80 ⬚C N 0.1−28 d, 71−95% N + SnBu3 N N SnBu3 H Ar Ar 18 aryl-1,2,4,5-tetrazines Synthesis of alkyl perfluoroalkanedithiocarboxylates and some aspects of their reactivity in cycloaddition reactions [161] R3 R3 RCS2R1 + R2 R2 R2 S r.t., 10 h R 30−85% R2 R1S R = CF3, C3F7; R1 = Et, Bn 2 dienes: R3 = H, R2 = Me; R2 = H, R3 = OSMT The intramolecular Diels±Alder reactions of photochemically generated trans-cycloalkenones [162] O hn, Pyrex 66−80% ( )n n = 1, 2 6 substrates O H ( )n H H H 92 References REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 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Ghosez L., Jnoff E., Bayard P., Sainte F. and Beaudegnies R. Tetrahedron 1999, 55, 3387. 160. Sauer J. and Heldmann D. K. Tetrahedron 1998, 54, 4297. 161. Portella C., Shermolovich Y. G. and Tschenn O. Bull. Soc. Chim. Fr. 1997, 134, 697. 162. Dorr H. and Rawal V. H. J. Am. Chem. Soc. 1999, 121, 10229. The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 3 3.1 Lewis-Acid-Catalyzed Diels±Alder Reaction INTRODUCTION The terms acid and base have been defined in different ways depending on the particular way of looking at the properties of acidity and basicity [1]. Arrhenius first defined acids as compounds which ionize in aqueous solution to produce hydrogen ions, and bases as compounds which ionize to produce hydroxide ions. According to the Lowry±Brùnsted definition, an acid is a proton donor and a base is a proton acceptor [2]. According to the Lewis definition, acids are molecules or ions capable of coordinating with unshared electron pairs, and bases are molecules or ions having unshared electron pairs available for sharing with acids [3]. To be acidic in the Lewis sense, a molecule must be electrondeficient. This is the most general acid±base concept. All Lowry±Brùnsted acids are Lewis acids but, in addition, the Lewis definition includes many other reagents such as boron trifluoride, aluminum chloride, etc. The discovery that Lewis acids can promote Diels±Alder reactions has become a powerful tool in synthetic organic chemistry. Yates and Eaton [4] first reported the remarkable acceleration of the reactions of anthracene with maleic anhydride, 1,4-benzoquinone and dimethyl fumarate catalyzed by aluminum chloride. The presence of the Lewis-acid catalyst allows the cycloadditions to be carried out under mild conditions, reactions with low reactive dienes and dienophiles are made possible, and the stereoselectivity, regioselectivity and site selectivity of the cycloaddition reaction can be modified [5]. Consequently, increasing attention has been given to these catalysts in order to develop new regio- and stereoselective synthetic routes based on the Diels±Alder reaction. Examples of the effects of Lewis-acid catalysts on the selectivities are reported in Scheme 3.1. This Lewis acid ability of increasing both the reaction rate and the selectivity of the cycloaddition is surprising, since in other catalyzed reactions an increase in the reaction rate is accompanied by a decreased selectivity according to the reactivity±selectivity principle. This apparently contradictory behavior of the Lewis acids has been explained theoretically [6,7]. Many Lewis-acid catalysts have been studied and used in the Diels±Alder reactions, ranging from the more commonly used strong Lewis acids such as AlCl3 , TiCl4 , SnCl4 , ZnCl2 , ZnBr2 , etc., to the milder lanthanide complexes and to the chiral catalyst. 100 Carbon Diels±Alder Reaction O O O + + H Reaction Conditions 150 ⬚C, 142 h AlCl3, 25 ⬚C, 17 h H para/meta 65:35 97:3 O O NOH O 80 ⬚C NOH H O O Yield (%) 20 97 H SnCl4, 20 ⬚C HON H O CO2Me + H + CO2Me Reaction Conditions ⬚C, DCM, 0 67 h DCM, AlCl3, 0 ⬚C, 1 h CO2Me H endo/exo 92:8 98:2 Scheme 3.1 This chapter will mostly deal with the applications of the Lewis-acid-catalyzed Diels±Alder reaction to organic synthesis and the influence of Lewis acids on reactivity, stereoselectivity and regioselectivity of the cycloadditions. 3.2 3.2.1 CARBON DIELS±ALDER REACTION Cycloadditions of Cycloalkenones Diels±Alder reactions of conjugated cycloalkenones provide a very important method for rapidly constructing complex polycyclic molecules. Since cycloalkenones are very poorly reactive dienophiles, acceleration by special physical and catalytic methods is required in order to avoid high reaction temperatures and long reaction times which often lead to low product yields [8]. A broad study of aluminum chloride-induced cycloadditions of cyclopentenones, cyclohexenones and cycloheptenones with 1,3-butadiene (1), isoprene Lewis-Acid-Catalyzed Diels±Alder Reaction 101 (2), (E)-piperylene (3) and 2,3-dimethyl-1,3-butadiene (4) (Figure 3.1) allowed all the reaction constraints to be determined, thus opening a straightforward route to the synthesis of hydrindanones, octalones and hydrobenzosuberones [9]. The diastereofacial selectivity in the catalyzed cycloadditions of 4-, 5- and 6substituted 2-cyclohexenones 5 (Figure 3.1) has been extensively studied and the results (Table 3.1) have been interpreted in terms of a unifying stereoelectronic pathway and conformational considerations rather than a mere consideration of steric factors [10±12]. Diene±dienophile interaction, as shown for 4-alkylsubstituted 2-cyclohexenones in Scheme 3.2, occurs in such a way that (in the absence of steric interference) an axial diene approach antiparallel to the pseudo axial bond at neighboring C(4), which creates an incipient fused O R1 6 R3 5 R R2 4 5 R = Me, i-Pr, t-Bu 1 R1 = R2 = R3 = H 2 R1 = Me, R2 = R3 = H 3 R1 = R2 = H, R3 = Me 4 R1 = R2 = Me, R3 = H Figure 3.1 Table 3.1 Facialselectivitya in the aluminium chloride catalyzed Diels±Alder reactions of 4-, 5-and 6-substituted 2-cyclohexenones 5 with dienes 1±3 Diene 1 2 3 R Me i-Pr t-Bu 55 90 49 67 91 61 100 100 100 Dienophile O R 1 2 3 96 97 96 92 92 98 97 91 97 O R 1 2 3 a 35 33 Expressed as % of anti Diels±Alder adducts. O R 102 Carbon Diels±Alder Reaction H H R O R H H H H H H H H H anti syn parallel H H O R H H H α H R H β H H O H H H O α β H syn anti antiparallel H H R H R H O H O H H H H H H H H H Scheme 3.2 cyclohexenone in half-chair conformation, is preferred over a parallel approach which produces the same ring in initial half-boat form. The adducts coming from Lewis-acid-catalyzed Diels±Alder reaction of 2-unsubstituted 2-cycloalkenones can epimerize at C-2 and therefore the trans adduct is sometimes the main reaction product. Highly anti-diastereofacial selective cycloaddition of isoprene (2) with 4isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocontrolled synthesis [13] of b-cadinene and (g2 -cadinene, Scheme 3.3). High antidiastereofacial selectivity also occurs in the Diels±Alder reaction of optically active cyclohexenones 6±9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14±16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. Bicyclic [6.4.0]dodecane systems have been prepared [17] by catalyzed and photochemical intermolecular cycloaddition of the cyclooct-2-en-1-ones 10 and 1,3-butadiene (1) and by catalyzed intramolecular cycloaddition of trienone 11 (Scheme 3.4). A strong dependence of the diastereofacial selectivity [18] on the substituents has been observed in the catalyzed cycloadditions of acyclic dienes with Lewis-Acid-Catalyzed Diels±Alder Reaction 103 O H + H H PhMe, AlCl3 60 ⬚C, 7 h 75% O H MeMgBr Ni(acac)2 PhH, 39% Me3SiO H H (i-Pr)2NH, BuLi, Me3SiCl CH2PPh3 Et3N, 89% H H H H H H Scheme 3.3 O O O O 6 7 8 9 H Figure 3.2 O O R O R R hν EtAlCl2 + 30% 56% H H 10 1 R = H, Me O O O R R PhH, Me2AlCl R + 25-55 ⬚C, 62-74% H R1 11 R, R1 = H, Me R1 major Scheme 3.4 H R1 104 Carbon Diels±Alder Reaction 4,4-disubstituted dienones 12 (Scheme 3.5). Whereas the cycloadditions of 1,3-butadiene (1) with dienones 12b and 12c showed a clear preference for the anti-diastereoselectivity (anti with respect to the C-4 ester group), a reversal syndiastereofacial selectivity was observed in the cycloaddition of dienone 12a. Similar results were observed in the cycloaddition with (E)-piperylene. O O CHO O CHO DCM, ZnCl2 + (CH2)nCO2Et CHO + r.t., 90% H (CH2)nCO2Et H (CH2)nCO2Et 1 12 A B 12 n a 0 b 1 c 2 A/B 0:100 63:37 84:16 Scheme 3.5 The presence of two substituents at C-4 also strongly influences the regioselectivity as shown in the cycloaddition of dienone 13 with isoprene (2) (Equation 3.1). In violation of the para-rule for Diels±Alder reaction, only meta-adduct was obtained [19,20]. O O H H Et2O, BF3 r.t., 22 d, 61% O + 13 O H PhH AlCl3, 63% H + H 3:1 H major The presence of the catalyst can also favor multiple Diels±Alder reactions of cycloalkenones. Two typical examples are reported in Schemes 3.6 and 3.7. When (E)-1-methoxy-1,3-butadiene (14) interacted with 2-cyclohexenone in the presence of Yb fod3 catalyst, a multiple Diels±Alder reaction occurred [21] and afforded a 1:1.5 mixture of the two tricyclic ketones 15 and 16 (Scheme 3.6). The sequence of events leading to the products includes the elimination of methanol from the primary cycloadduct to afford a bicyclic dienone that underwent a second cycloaddition. Similarly, 4-acetoxy-2-cyclopenten-1-one (17) (Scheme 3.7) has been shown to behave as a conjunctive reagent for a one-pot multiple Diels±Alder reaction with a variety of dienes under AlCl3 catalysis, providing a mild and convenient methodology to synthesize hydrofluorenones [22]. The role of the Lewis acid is crucial to facilitate the elimination of acetic acid from the cycloadducts. The results of the reaction of 17 with diene Lewis-Acid-Catalyzed Diels±Alder Reaction O O R H 14 H H 110 ⬚C, 110 h 160 ⬚C 24 h 47% O R PhMe, Yb(fod)3 + O 105 R + H H 16 60:40 15 R = OMe 14 Yb(fod)3 PhMe O R PhMe, Yb(fod)3 100 ⬚C, 7 h, 88% H H Scheme 3.6 4 are reported in Scheme 3.7. 4-Acetoxy-2-cyclopenten-1-one (17) behaves like a synthetic equivalent of the cyclopentadienone [23]. In a practical sense the instability of the alkoxy-, acyloxy-and silyloxy-substituted cycloadducts under Lewis-acid-catalyzed conditions may sometimes be a H O H O H H + O 40 ⬚C, 18.5 h, 62% H OAc 4 H + O H O H AlCl3 H H OAc Scheme 3.7 H H H 4 H H PhMe, AlCl3 + 17 H O 106 Carbon Diels±Alder Reaction serious problem in the Diels±Alder reaction, as well as in further transformations of the adducts. Diethylphosphoryloxybutadienes such as 19 and 20 (Figure 3.3), and the cycloadducts derived from them, are significantly stable, thus retaining a high degree of synthetic usefulness [24]. OPO(OEt)2 OPO(OEt)2 20 19 Figure 3.3 3.2.2 Heterocyclic Dienophiles Strong effects of the catalyst on the regioselectivity have been observed in the cycloadditions of a variety of heterocyclic dienophiles. Some results of the BF3 catalyzed reactions of quinoline-5,8-dione (21) and isoquinoline-5,8-dione (22) with isoprene (2) and (E)-piperylene (3) [25], and of the cycloadditions of 4quinolones (23a, 23b) as well as 4-benzothiopyranone (23c) with 2-piperidinobutadienes, are reported [26] in Scheme 3.8 and Equation 3.2. The most marked O O DCM 5d + N + N N 3 O O O 21 O r.t. BF3 Et2O 47:53 1:99 O DCM 5d O + N 2 N O O r.t. BF3 Et2O O O O 22 O DCM + N 46:54 64:36 5d + N O 3 O r.t. BF3 Et2O Scheme 3.8 N 38:62 95:5 Lewis-Acid-Catalyzed Diels±Alder Reaction O 107 R O H R BF3, DCM + X r.t., 1 h N X H O 3:2 23 a X = NCO2Et b X = NCbz cX=S R = i-Pr, t-Bu, Cy influence was observed in the reaction of 21 with (E)-piperylene. This has been rationalized by considering the secondary orbital interactions of piperylene's HOMO with the LUMOs of catalyst±dienophile complexes. Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels±Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-1,4-dimethylbutadiene, 2,3-dimethylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regioselective and totally endo-anti-diastereoselective (anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. CO2Me R+ O R O N DCM + CO2Me O N O A R Me Me H2 C H2 C Cat ZnCl2 ZnCl2 T (⬚C) 60 0 60 0 t (h) 24 4 18 36 N O O 24 CO2Me R B A/B Yield (%) 2 74 25 71 2.3 75 15.2 66 Scheme 3.9 (E)-Azlactones are among the most important precursors of a-amino acids [29], but the less stable (E)-isomer easily isomerizes to the (Z)-isomer affording, as a consequence, in the Diels±Alder reaction complex mixtures of cycloadducts. The use of some heterogeneous catalysts (SiO2 ±Et2 AlCl, SiO2 ±TiCl4 , SiO2 ±ZnCl2 ) reduces the E/Z isomerization [30] and allows the selectivity of the Diels±Alder reaction to be improved, as shown for the chiral azlactone 25 (Equation 3.3). The best control has been obtained with SiO2 ±ZnCl2 . Equation 108 Carbon Diels±Alder Reaction CO2Me O N O R N O R = Me, R O H2C BuLi − 20 ⬚C H R R Pr Pr O Bu4NH2PO4 O EtOH, ∆, 4 h N HO O R Bu 55-60% overall yield Scheme 3.10 O O O O O H O R Ph R O R1 N R R N + Ph R1 O major product 25 R = Me, R1 = H 20 ⬚C, 24 h SiO2-ZnCl2 27% 81% R = R1 = Me 20 ⬚C, 24 h SiO2-ZnCl2 78% 94% 3:3 3.3 reports the percentages of the major component of the reaction mixtures obtained in the cycloadditions with isoprene (2) and 2,3-dimethylbutadiene (4) under thermal and SiO2 ±ZnCl2 catalyzed conditions. Chiral tricyclic compounds have been prepared by thermal and Eu fod3 catalyzed cycloadditions of furanosidic a,b-unsaturated aldehydes 26±29 (Figure 3.4) with cyclopentadiene (18) [31]. The diastereofacial selectivity depends markedly on the stereochemistry of the anomeric benzyloxy and methoxy groups. 3.2.3 Rare Earth Metals and Scandium Triflates Rare earth metals and scandium trifluoromethanesulfonates (lanthanide and scandium triflates) are strong Lewis acids that are quite effective as catalysts in Lewis-Acid-Catalyzed Diels±Alder Reaction O O OBn O OBn 109 OSiMe2Thx O O O H OMe O H H 26 OSiMe2Thx O OMe H 28 27 29 Figure 3.4 the cycloadditions of carbonyl-containing dienophiles. These compounds were expected to act as strong Lewis acids because of their hard character and the electron-withdrawing trifluoromethanesulfonyl group, and to have a strong affinity toward carbonyl oxygen. These catalysts, such as Yb OTf3 , have been used successfully [32] in the reactions of cyclopentadiene (18) with acyclic aldehydes and ketones, quinones and cycloalkenones, and have also been used in the inverse electron-demand cycloadditions. It must be emphasized that a catalytic amount of catalyst is enough to accelerate the reactions and that the catalyst can be easily recovered and reused. Scandium triflate [33] is a more active catalyst than the lanthanide triflates and the cycloadditions can also be carried out in aqueous media (Chapter 4). The catalyst is easily recovered from the aqueous layer after the reaction is completed, and can be reused. Some of the cycloadditions carried out in DCM and catalyzed by Sc OTf3 are summarized in Table 3.2. Table 3.2 Reaction yield (%) of Diels±Alder reactions catalyzed by Sc OTf3 (DCM, 0 8C, 10 mol % cat) Dienophile O O N O O 90 86 95 89 91 88 96 83 92 83 62 O O 110 Carbon Diels±Alder Reaction Whereas lanthanide triflates are strong Lewis acids, lanthanide complexes such as Yb fod3 and Eu fod3 are mild catalysts that can be used when the cycloaddition involves acid-sensitive reagents and/or cycloadducts [34]. Diiodosamarium [35] is a mild catalyst that can be used with success as an alternative to Eu fod3 or Yb fod3 in both all carbons and hetero-Diels±Alder reactions (Equations 3.4 and 3.5). OMe O H H , SmI2 O −30 ⬚C, 2 h, 80% , SmI2 25 ⬚C, 24 h, 92% CO2Me 18 O endo/exo = 9:1 R H OMe DCM, SmI2 + H C 3:4 endo/exo = 4:1 OMe O H OSMT −30 ⬚C, 80−98% O TMSO TFA R O O R 3:5 R = Ph, Ph-CH=CH-, 2-Fu 3.2.4 Bulky Lewis Acids Regio- and stereochemical control in the catalyzed Diels±Alder reactions also depends on the chelating and non-chelating ability of Lewis-acid catalysts. These two types of catalysts can lead to an opposite diastereoselectivity depending either on the ability of Lewis-acidic reagents to form intermediate chelates that are attacked stereoselectively from the less hindered site (chelation control) or on the reagent incapability of chelation (non-chelation control), the stereoselectivity being governed by electronic and/or steric factors [36]. Bulky methylaluminum-bis-(4-methyl-2,6-di-tert-butylphenoxide) (MAD) and methylaluminum-bis-(4-bromo-2,6-di-tert-butylphenoxide) (MABR) are examples of efficient non-chelating Lewis acids and show a remarkably high regio- and stereochemical control, as shown in the cycloaddition of unsymmetrical fumarate [37] 30 with 2-substituted 1,3-butadienes (Scheme 3.11) and of acrylate [36] 31 with cyclopentadiene (18) (Scheme 3.12). The stereoselectivity in these cases is controlled by the incapability of chelation of the bulky catalysts. 3.2.5 Heterocyclic Dienes Highly functionalized benzenes and naphthalenes have been prepared by cycloaddition of zirconacyclopentadiene 32 and its benzoderivative 33 [38] with Lewis-Acid-Catalyzed Diels±Alder Reaction R CO2Me+ t-BuO2C 111 R Solv., Cat. −78 to −20 ⬚C, 1−72 h 30 A R Me Catalyst − Et2AlCl MAD MAD OSiMe3 − Et2AlCl MAD MAD CO2t-Bu CO2Me R + CO2t-Bu Solvent PhMe DCM DCM PhMe A/B 56:44 44:56 14:86 20:80 PhMe DCM DCM PhMe 48:52 44:56 1:99 17:83 CO2Me B Scheme 3.11 DCM, CatT. OR* + −78 to −20 ⬚C H O H+ + CO2R* CO2R* 31 18 A Cat. (equiv.) TiCl4 (1) SnCl4 (2) EtAlCl2 (2) R* = O MAD (2) MABR (2) O B endo/exo 97:3 97:3 99:1 95:5 89:11 + CO2R* CO2R* H H C A/B 97:3 97:3 86:14 5:95 5:95 Yield (%) 83 97 97 96 97 Scheme 3.12 alkynes [39] in the presence of a stoichiometric amount of CuCl/LiCl. Equations 3.6 and 3.7 report the results of the cycloadditions with DMAD. In the absence of copper salts, the diene was unreactive. R3 R1 R4 R Zr R R2 + MeO2C CO2Me CuCl-LiCl r.t., 54−71% R1 32 R = Ph; R1, R2, R3, R4 = Me, Et, Bu, Ph, SiMe3 R2 CO2Me R3 CO2Me R4 3:6 112 Carbon Diels±Alder Reaction Et Et Et CO2Me + MeO2C Ph Et CuCl-LiCl 54% Zr 3:7 MeO2C Ph CO2Me 33 Intramolecular cycloadditions of furans are a useful method for creating an oxygenated cyclohexane ring in rigid cycloadducts. Thus, a MeAlCl2 -catalyzed intramolecular reaction [40] of compounds 34 leads stereoselectively to tricyclic cycloadducts (Equation 3.8). The reaction yield is strongly dependent on the quantity of the catalyst and the type of substituent at the olefinic double bond. Cycloadduct 35 (R R2 Me, R1 R3 R4 H) was then converted [40b] into 1,4-epoxycadinane (36). R1 R2 R MeAlCl2 R3 O R1 R2 R4 4-99% O O R O R4 34 R3 3:8 H O 35 36 R, R1, R2, R3, R4 = H, Me The catalyst played an important role in the asymmetric synthesis of Corey lactone based on high diastereofacial selective Diels±Alder reaction between chiral acrylate 37 and 5-benzyloxymethylcyclopentadiene [41] (Equation 3.9). The cycloadduct 38 was then converted into chiral Corey lactone [42] by a three-step procedure. BnO OR* O 37 3.2.6 BnOH2C + O DCM, TiCl4 −15 ⬚C, 79% de 94% R* = O 3:9 CO2R* 38 Sulfinyl Group Containing Dienes and Dienophiles It has been shown that the sulfinyl group present as chiral auxiliary either in dienophiles or in dienes is very useful for controlling the enantio- and diastereofacial selectivity in the asymmetric Diels±Alder reaction [43]. A wide variety of enantiomerically pure cyclohexadienedicarboxylates has been produced by cycloaddition of the sulfinylmaleate 39 with several dienes under catalyzed Lewis-Acid-Catalyzed Diels±Alder Reaction 113 conditions (Equation 3.10). The cycloadduct then eliminates spontaneously the sulfinyl group at room temperature [44]. O S Tol SOTol R TiCl , DCM, −78 ⬚C R 4 CO2Bn + CO2Me 66−91%, ee 83−96% R1 CO2Bn CO2Me R1 R CO2Bn R1 CO2Me r.t. 3:10 R, R1 = H, Me, OMe 39 Sulfinyldiene 40 reacts, regio- and stereoselectively, with methylacrylate in the presence of a catalyst, affording carbomethoxycyclohexene derivatives [45]. Among the catalysts examined, the best was lithium perchlorate used as a suspension in DCM; it gave only endo isomers in 70 % yield in a 96:4 d.e. ratio (Equation 3.11). O S CO2Me + R* DCM, LiClO4 R O S + 25 ⬚C, 7h, 70%, d.e.: 96:4 R O S CO2Me CO2Me OMe OMe OMe 3:11 40 HO R* = Sulfinylacrylate 41 has been successfully used in the enantioselective synthesis of pseudo-sugar [46, 47]. Cycloaddition of (S)-3-(2-pyridylsulfinylacrylate) (41) with furan and 3,4-dibenzyloxyfuran under Et2 AlCl catalysis afforded cycloadducts 42, 43 and 44 (Equation 3.12) which were converted into pseudo-mannopyranoses 45, 46 and 47 (Figure 3.5). BnO CO2Men Py S O 41 O O BnO DCM, Et2AlCl O BnO −20 ⬚C, 5d, 79% BnO DCM, Et2AlCl CO2Men SOPy 42 BnO CO2Men BnO SOPy 43 Men = (−)menthyl Py = 2-pyridyl O O + CO2Men SOPy 44 3:12 114 Carbon Diels±Alder Reaction R R R R R R R 45 R = OAc NHR R R R R R 46 R R 47 Figure 3.5 3.2.7 Transition-Metal-Based Catalysts The most commonly used traditional Lewis acids are halides of aluminum, boron, titanium, zinc, tin, and copper. However, there are also more complex Lewis-acids that are quite effective catalysts that can be easily modified for carring out enantioselective processes, by incorporating chiral ligands. These can overcome some limitations associated with the use of classical Lewis acids [47]. Ferrocenium hexafluorophosphate (48) and catecholboronbromide (49) (Figure 3.6) are efficient catalysts that have been tested in the cycloadditions of cyclic and acyclic dienes with a variety of dienophiles [48]. Catalyst 48 is less active than 49, but is less corrosive. Transition-metal-based Lewis acids such as molybdenum and tungsten nitrosyl complexes have been found to be active catalysts [49]. The ruthenium-based catalyst 50 (Figure 3.6) is very effective for cycloadditions with aldehyde- and ketone-bearing dienophiles but is ineffective for a,b-unsaturated esters [50]. It can be handled without special precautions since it is stable in air, does not require dry solvents and does not cause polymerization of the substrates. Nitromethane was the most convenient organic solvent; the reaction can also be carried out in water. The cyclopentadienyl triflate complexes of zirconium and titanium 51 and 52 (Figure 3.7) are also active catalysts [51]. Their activity has been tested in a wide variety of dienes and dienophiles. It is noteworthy that even at low catalyst loadings, rate accelerations between 103 and > 105 times have been observed. No special precautions were taken to dry the solvents or the substrates, in contrast with the traditional Lewis acids which require either predried solvents or high catalyst loadings. O Fe 48 Figure 3.6 PF6 B Br O 49 [Ru(salen)(NO)(H2O)] SbF6 50 Lewis-Acid-Catalyzed Diels±Alder Reaction 115 [Zr(Cp)2(CF3SO3)2THF] [Ti(Cp)2(CF3SO3)2] 51 52 Figure 3.7 3.2.8 Heterogeneous Catalysis Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a,b-unsaturated aldehydes with several dienes. It has been prepared from (Z5 -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels±Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. CHO R1 + R R = H, Me R2 R1 DCM, Cat. 53 R −78 ⬚C to r.t., 24 h, 60−97% R 2 CHO 3:13 R1, R2 = H, Me Several aluminum- and titanium-based compounds have been supported on silica and alumina [53]. Although silica and alumina themselves catalyze cycloaddition reactions, their catalytic activity is greatly increased when they complex a Lewis acid. Some of these catalysts are among the most active described to date for heterogeneous catalysis of the Diels±Alder reactions of carbonyl-containing dienophiles. The SiO2 ±Et2 AlCl catalyst is the most efficient and can be O N H P O OBn SO2 O Al CF3 N Fe OC O OTf CO Me N SO2 53 CF3 55 Figure 3.8 116 Carbon Diels±Alder Reaction recovered and stored without a great loss of catalytic activity even if kept in the open air for a month. Other examples have been reported in Section 3.2.2. 3.2.9 Chiral Catalysts Asymmetric induction in the intermolecular Diels±Alder cycloaddition reactions can be achieved with chirally modified dienes and dienophiles as well as with chiral Lewis-acid catalysts [54±56]. Aluminum-based catalyst (S,S)-diazaaluminolidine 54 promoted the cycloaddition [57] between 5-(benzyloxymethyl)-1,3-cyclopentadiene and 3-acryloyl-1, 3-oxazolidin-2-one, leading to the cycloadduct in high yield and high enantiomeric excess (94 %) (Equation 3.14). OBn BnO O DCM, Cat.* 54 (Ar = Ph) + N O O −78 ⬚C, 18 h, 93%, ee = 94% O O N O 3:14 Ar Ar N SO CF Cat.* =F3CO2S N Al 2 3 54 The transition state assembly 55 (Figure 3.8), that rationalizes the stereochemistry of the cycloadduct, is consistent with the structure of the chiral catalyst determined by an X-ray diffraction study. Interestingly it has been shown [58] that in the cycloadditions of maleimides 56 with 2-methoxy-1,3-butadiene, the enantioselection depends on the bulkiness of Ar and Ar1 groups of catalyst 54 and dienophile 56, respectively (Scheme 3.13). The importance of the bulky Ar1 O H N Ar1 C7H8, −78 ⬚C, Cat.* 54 + OMe MeO O 56 Ar (54) Ar1 (56) (ee %) Ph Ph Ph Ph o-MeC6H4 o-t-Bu-C6H4 35 58 52 O N Ar1 H O Ar (54) Ar1 (56) 3,5-Me2C6H3 Ph 3,5-Me2C6H3 o-MeC6H4 3,5-Me2C6H3 o-t-Bu-C6H4 Scheme 3.13 (ee %) 62 93 95 Lewis-Acid-Catalyzed Diels±Alder Reaction 117 groups at the nitrogen atom of 56 is demonstrated by the fact that the cycloaddition of the same diene (2-methoxy-1,3-butadiene) with maleic anhydride, catalyzed by 54 (Ar Ph), produces a racemic adduct. This phenomenon can be readily explained if the coordination of the catalyst to maleic anhydride occurs at carbonyl oxygen lone pair b rather than at lone pair a. Coordination at lone pair b places the dienophilic double bond so far from the chiral catalyst that no enantioselection can be expected. In the case of maleimides, coordination of the catalyst to lone pair b is effectively blocked by the bulky Ar1 group. The transition state assembly that leads to the observed stereochemistry of the cycloadduct is depicted in formula 57 (Figure 3.9). OMe O a O b N Me O O N H Me R SO2 O H Me N Al CF3 Me SO2 CF3 Me 57 Figure 3.9 In contrast, modest enantioselection has been observed in the asymmetric Diels±Alder reaction between cyclopentadiene (18) with methylacrylate and methylpropiolate catalyzed by chiral organoaluminum reagents 58 [59] (Equation 3.15) prepared from trimethylaluminum and (R)-()-3,30 -bis(triphenylsilyl)-1,10 -bi-2-naphthol [60]. The reaction was highly endo-diastereoselective. + CO2Me DCM, Cat.* 58, 0 ⬚C, 9 h 35−83%, ee = 36−77% + CO2Me CO2Me 18 SiAr3 3:15 O O Al Me SiAr3 58 Ar3 = Ph3, (t-Bu,2 Ph), (4-t-BuC6H4)3, (3,5-Et2C6H3)3 118 Carbon Diels±Alder Reaction O B Br Ar N O Br B Br Ar N Br Ar Ar 59 59a Figure 3.10 Cationic oxazaborinane 59 (Figure 3.10) is a chiral super-Lewis-acidic catalyst recently described by Corey and coworkers [61]. The catalyst is in equilibrium with 59a and the oxazaborinane system 59 ! 59a is unstable and undergoes gradual decomposition at temperatures above 60 8C. A more active catalyst system is the tetraarylborate salt 59 BC6 H3 3, 5 CF3 2 4 which allows the cycloadditions of cyclopentadiene (18) and a,b-unsaturated aldehydes to occur with a high level of stereoselectivity and enantioselectivity (Equations 3.16 and 3.17). O + R Cat.* 59 B[C6H3−3,5(CF3)2]4 H DCM, −94 ⬚C, 2 h, 97−99% R1 18 CHO 3:16 R R1 exo:endo = 88−98:12−2 R = Br, Me; R1, = H, Me O Br H Br Cat.* 59 B[C6H3−3,5(CF3)2]4 + 3:17 CHO DCM, −94 ⬚C, 0.5−2 h 99%; ee 93−98% Chiral titanium- and scandium-based catalysts (61 and 62, Figure 3.11) were used to accelerate the cycloadditions of acyl-1,3-oxazolidin-2-ones 60 (Scheme 3.14) with butadiene, isoprene and cyclopentadiene. The cycloadditions R1 O O N Cat.* 61, PhMe, 0 ⬚C-r.t., 12−48 h 81−93% R = H, R1 = H, Me R O R = Me, Ph Cat.* 62 DCM, 0 ⬚C, 10 h 83−89% 60 R1 R O O C O N O O C N O ee (endo) 92−97% ee 93−96% Scheme 3.14 Lewis-Acid-Catalyzed Diels±Alder Reaction 119 N Ph Ph Ph O O O O Ph H O TiCl2 O H Ph Sc(OTf)3 N 61 62 Figure 3.11 occurred with an excellent enantiomeric excess and are a valuable method for preparing chiral cyclohexene and norbornene carboxylic acid derivatives [62,63] (Scheme 3.14). The high level of enantioselection is explained considering that the complexation of dienophile occurs either as depicted in 63 or as in 64 (Figure 3.12), the re-face of dienophile being always that preferentially attacked. Titanium-based catalyst 61 was prepared (Equation 3.18) by the alkoxy exchange between dichloroisopropoxytitanium(IV) and a chiral 1,4diol derived from (2R, 3R)-tartrate in the presence of molecular sieves MS4A, O O Ph O Me O Ti Ph O O Me O O R O N O O Ti O O O N R 64 63 Figure 3.12 Ph Ph O O R R Ph Ph Ph OH OH Ph Ph + TiCl2(Oi-Pr)2 Ph O O O O Ph Ph 61 TiCl2 + 2 i-PrOH 3:18 120 Carbon Diels±Alder Reaction and scandium-based catalyst 62 was prepared from scandium triflate, R-()1,10 -bi-2-naphthol[(R)-BINOL] and a tertiary amine. The enantioselection depends strongly on the nature of the amine: the best results were obtained with cis-1,2,6-trimethylpiperidine. Binaphthol-derived titanium complexes [64], prepared from chiral ligands 65 (Figure 3.13), also performed very well in the cycloadditions of conjugated aldehydes with cyclic and acyclic dienes. Judging from the absolute configurations of endo and exo adducts, this catalyst should cover the re-face of carbonyl on its anti-coordination to s-trans a,b-unsaturated aldehydes, and hence dienes should approach selectively from the si-face. CF3 R OH OH OH OH O O B O H O O B H O O CF3 Ph R 68 65 69 Figure 3.13 When the iron-based catalyst 66 was used, a high level of enantiomeric excess in the cycloadditions between cyclopentadiene (18) and a,b-unsaturated aldehydes [65] was observed. The cycloadditions were carried out in the presence of 2,6-di-t-butylpyridine (Scheme 3.15) which was added to scavenge residual acid impurities. R + R1 18 H O DCM, 2,6-t-Bu2Py, Cat.* 66 −40 to −20 ⬚C, 16−20 h, 12−87% ee: 88−95% R CHO R1 R = H, Me, Et, Br; R1 = H, Me (C6F5)2P Fe L BF4 P(C6F5)2 L = CH2=CH-CHO (R, R) 66 Scheme 3.15 Lewis-Acid-Catalyzed Diels±Alder Reaction 121 Table 3.3 Diels±Alder reactions of a,b-unsaturated aldehydes (67) with cyclopentadiene (18) catalyzed by (R)-BLA 68 and (R)-BLA 69 O R DCM, −78 ⬚C + R 1−24 h. R1 R1 + CHO 67 R exo endo 18 (R)-BLA 68 Dienophile R R1 H R Br, R1 H R Me, R1 H R Et, R1 H R H, R1 Me R R1 Me R H, R1 Et R H, R1 CO2 Et Yield (%) 91 >99 >99 >99 12 99 (R)-BLA 69 endo/exo ee (%) Yield (%) 9:91 99:1 99:1 97:3 11:89 99:1 CHO R1 40 (R) 99 (S) 99 (R) 92 36 (R) 98 endo/exo ee (%) 84 99 3:97 90:10 95 (S) 99 (R) 94 90 73 91 10:90 98:2 9:91 2:98 95 (S) 96 98 95 (S) Brùnsted acid-assisted chiral Lewis acids (BLA) are an interesting class of catalysts which efficiently induce asymmetry in the Diels±Alder reaction through the combination of intramolecular hydrogen bonding and attractive ± donor±acceptor interactions between the dienophile and the chiral ligand in the transition state by hydroxy aromatic groups present in chiral Lewis acids [66]. The geometry of the catalyst is of great importance for a high level of asymmetric induction. Yamamoto and coworkers [67] have synthesized several BLAs by using different chiral ligands and various boron compounds. Examples are (R)-BLA 68 and (R)-BLA 69 (Figure 3.13). Table 3.3 summarizes the results of the Diels±Alder reactions of a,b-unsaturated aldehydes 67 and cyclopentadiene (18) catalyzed by these catalysts. The best catalyst was 69 because it activates the Diels±Alder reactions of both a- and b-substituted enals and shows an absolute stereopreference opposite to that found by using 68. This means that the presence of the electron-withdrawing trifluoromethyl groups affects the asymmetric induction of the catalyst. The efficiency of these catalysts was also tested in intramolecular cycloadditions (Equation 3.19). Only endo adduct 71 with 80 % ee and 95 % yield was obtained from trienal 70. This result was much better than the 74 % yield, 46 % ee, exo/endo 1:99 previously given by a chiral acyloxyborane-catalyzed reaction [68]. 122 Hetero-Diels±Alder Reaction H O O DCM, Cat.* 69 H −40 ⬚C, 95%, ee 80% H 3:19 H 71 70 3.3 HETERO-DIELS±ALDER REACTION 3.3.1 Normal Diels±Alder Reactions. Synthesis of Pyrones and Thiopyrans Hetero-Diels±Alder reactions provide one of the most convenient tools for synthesizing heterocyclic compounds [69,70]. Dihydropyrans [71] and 4-dihydropyranones [72] have been prepared by BF3 or Me2 AlCl catalyzed Diels±Alder reactions of alkyl and aryl aldehydes with dienes 72 and 73 (Equations 3.20 and 3.21). Allylic bis-silanes are useful building blocks for synthesizing molecules of biological interest [73]. 4-Pyranones have been obtained by cerium ammonium nitrate (CAN) oxidation of the cycloadducts. O R H SiMe3 DCM, BF3, −10 ⬚C, 0.5 h SiMe3 41−62% + Me3Si O Me3Si R 3:20 72 R = Me, Et, i-Pr, i-Bu, Ph OSi-(i-Pr)3 O R H PhMe, BF3 or Me2AlCl + OSi-(i-Pr)3 + −78 ⬚C, 63−94% R 73 OSi-(i-Pr)3 O R O 3:21 O DMF, CAN R O 75−95% R = Me-CH=CH, Ph, Ph-CH=CH, 2-Fu, C6H11, CH2OSPT The Diels±Alder reaction of aldehydes 74 with dienes 75 in the presence of chiral acyloxyborane (CAB) catalysts 76 provides enantioselectively chiral 4dihydropyranones (Equation 3.22) after CF3 CO2 H treatment of the cycloadducts [74]. Lewis-Acid-Catalyzed Diels±Alder Reaction 123 O OMe R1 O + R H OSMT 74 CH3CH2CN, Cat.* 76 R1 R1 CF3CO2H −78 ⬚C, 4-9 h, 5−92% ee 52−97% R O R1 75 Oi-Pr O R = Ph, 4-MeC6H4, Me-CH=CH, Ph-CH=CH R1 = H, Me, Ph R2 = substituted phenyl 3:22 CO2H O O Oi-Pr O O B R2 76 The enantioselection depends greatly on the nature of the R2 group at the boron atom, and the ee values were as high as 97 %. High enantioselectivity was observed in the synthesis of 4-dihydropyranones, based on the Diels±Alder reactions of aldehydes 74 and Danishefsky's diene, catalyzed by a BINOLTi(O-i-Pr4 -derived catalyst [75] (Equation 3.23). O OSMT O R + CF3CO2H ⬚C, DCM, −20 40 h 55−88%, ee 92−97% H 74 (R)-BINOL/Ti(Oi-Pr)4 O H R 3:23 OMe R = Fu, n-C8H17, BnOCH2, TBSOCH2CH2 The adduct derived from (a-benzyloxyacetaldehyde (97 % ee) is an important intermediate en route to compactin and mevinolin [76]. In contrast, modest enantioselectivity was attained when the cycloadditions were catalyzed by a chiral BINOL-ytterbium-derived catalyst [77]. Pyridines were used as additives, and the best enantioselection (93 % ee) was attained only in the case of pmethoxybenzaldehyde using 2,6-lutidine. Dihydrothiopyrans have also been prepared by cycloaddition between a,bunsaturated thioketones and carbonyl-activated dienophiles under Lewis-acid catalysis [78]. A marked dependence of the reaction yield on the catalyst was observed. The results of the cycloaddition reaction of thioketone 77 with methyl metacrylate, catalyzed by different catalysts, are illustrated in Equation 3.24. 3.3.2 Inverse Diels±Alder Reactions. Synthesis of Pyranes Lewis-acid catalyzed inverse electron-demand Diels±Alder reactions between conjugated carbonyl compounds and simple alkenes and enolethers also allow dihydropyranes to be prepared. SnCl4 -Catalyzed cycloaddition of 124 Hetero-Diels±Alder Reaction Ph CO2Me S Ph Et2O, 25 ⬚C, 0.2 h + Ph S CO2Me Ph cis + trans 77 Cat. − ZnCl2 i-PrOAlCl2 AlCl3 EtAlCl2 3:24 Yield (%) 68 57 75 77 93 methyl-2-oxo-3-alkenoates 78 with a variety of alkenes [79] afforded dihydropyran derivatives 79 (Equation 3.25). R1 R2 R1 R R R3 + O MeO2C R4 R6 DCM, SnCl4, 0 ⬚C, R2 3h 15−96% R5 O MeO2C 78 R3 R4 R5 R6 3:25 79 R, R1, R2, = H, Me, OMe, Ph; R3, R4, R5, R6 = H, Me, Et, Bu, −(CH2)4− Substituted 3,4-dihydropyranes were also prepared by Diels±Alder reactions between (E)-4-oxobutenoate 80 and vinylethers [80] under iron(III) 2-ethylhexaonate, a mild and economical catalyst (Equation 3.26). Diastereomeric excess as high as 98 % was observed. Cycloadducts with a 2,4-cis-configuration were preferred. CO2Et CO2Et OR + O 80 23 ⬚C, 14 d Cat = Fe(BuEtCHCO2)3 78−80%, de = 98% CO2Et 3:26 + O OR O OR major Inverse electron-demand Diels±Alder reaction of (E)-2-oxo-1-phenylsulfonyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the R1 group of the dienophile, and the best result was obtained when R1 was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2 -symmetric chiral Cu(II) complexes 83 (Scheme 3.16). Lewis-Acid-Catalyzed Diels±Alder Reaction 125 R R OR1 + PhO2S Cat.*, DCM, −30 to −78 ⬚C O 6−24 h, 77−92% 81 ee 59−97% R1O SO2Ph O 3:27 R = Me, i-Pr, Ph; R1 = Et, i-Pr, i-Bu Ph O Ph O X Cat.* = Ti O O Ph X = Cl, Br X Ph R O (MeO)2P O OEt DCM, −78 ⬚C Cat. 83 84−100% ee 99% R (MeO)2P 82 DCM, −78 ⬚C Cat. 83 79−100% ee 90−97% OEt O R (MeO)2P R = Me, i-Pr, OEt, Ph O O O O OsO4 t-BuOH-H2O 50% H H O Sm(OTf)3-MeOH ∆, 91% R R HO H R = Me O O OEt R = Me HO2C O 2 2 O O O N Cu 2X N Me3C N Cu X = OTf, SbF6 Scheme 3.16 2X N Ph CMe3 83a O Ph 83b 126 3.3.3 Homo-Diels±Alder Reaction Pyrones and Triazines as Dienes The 2-pyrones can behave as dienes or dienophiles depending on the nature of their reaction partners. 3-Carbomethoxy-2-pyrone (84) underwent inverse Diels±Alder reaction with several vinylethers under lanthanide shift reagentcatalysis [84] (Equation 3.28). The use of strong traditional Lewis acids was precluded because of the sensitivity of the cycloadducts toward decarboxylation. It is noteworthy that whereas Yb OTf3 does not catalyze the cycloaddition of 84 with enolethers, the addition of (R)-BINOL generates a new active ytterbium catalyst which promotes the reactions with a moderate to good level of enantioselection [85]. O O CO2Me R1 + X O R2 DCM, Ln(hfc)3, 20 ⬚C O 56−98% CO2Me R1 3:28 X R2 84 Ln = Eu, Pr X = OR, SR, OSMT 2,5-Disubstituted pyridines [86] 87 have been prepared by catalyzed cycloaddition of 4-methyl-1,2,3-triazine 85 with aldehyde enamines 86 (Equation 3.29). The best yields were obtained when ZnBr2 was used as catalyst. HC CHR N + 86 CHCl3, ZnBr2, 90 ⬚C N N N 2 h, 23−82% 85 R N 3:29 87 R = Ph, Bn, Ph(CH2)2−, Me(CH2)n− [n = 2, 3, 5, 10] 3.4 HOMO-DIELS±ALDER REACTION The homo-Diels±Alder reaction is a 2 2 2 cycloaddition of a 1,4-diene with a dienophile which produces two new bonds and a cyclopropane ring. This reaction is an example of a multi-ring-forming reaction that to date has found few applications in synthesis, since the use of 1,4-dienes has been limited mainly to bridged cyclohexa-1,4-dienes and almost exclusively to norbornadiene. Lewis-acid catalysts accelerate homo-Diels±Alder reactions and increase the selectivity for the [2 2 2] vs. 2 2 cycloaddition. A cobalt-based catalyst, prepared by reducing Co acac3 with diethylaluminum chloride in the presence of the bidentate ligand 1,2-bis(triphenylphosphino)ethane, accelerates [87] the cycloadditions of norbornadiene (88) with a variety of acetylenes (Equation 3.30). Lewis-Acid-Catalyzed Diels±Alder Reaction 127 PhH, Co(acac), Et2AlCl + H C C R DIPHOS, 1−24 h, 10−95% 3:30 R 88 89 R = H, Me, Et, i-Pr, Bu, t-Bu, Ph, CH2CH(OAc)CH2CH3, (CH2)4-OPMB, (CH2)3-OSMDBT This route provides a convenient method for synthesizing deltacyclenes 89 which have been proven to be useful in the synthesis of highly strained unnatural products of theoretical interest [88]. Diels±Alder reactions of norbornadiene (88) have been successfully activated by a nickel catalyst [89] (Scheme 3.17). A marked influence of the catalyst on the endo±exo diastereoselectivity has been observed. O ( )n Ni(COD)2, Ph3P, 80 ⬚C, 24 h 56% (n = 1), 23% (n = 2) H H ( )n + SOPh H SOPh Ni(COD)2, Ph3P, r.t., 62%, 2 d 88 O SOPh H endo exo 7:1 O + O H (CH2Cl)2 exo endo O (Ph3P)2Ni(CO)2, 80 ⬚C, 90% Ni(acac)2, Et3Al, 2 Ph3P, r.t., 62% 2:1 19:1 Scheme 3.17 An example that illustrates the influence of the nickel catalyst on the reaction yield is the cycloaddition between tricyclo [5.3.1.04, 9 ]-undeca-2,5-diene (90) and dimethylacetylenedicarboxylate (Equation 3.31). Whereas a thermal process afforded cycloadduct 91 in an unsatisfactory yield (22 %), the catalyzed process 128 Cationic Diels±Alder Reaction E E E Ni(CN)2(PPh3)2 + 3:31 45% E = CO2Me E 90 91 increased the yield up to 45 %. This reaction has been used to construct the didehydrohomoiceane skeleton [90]. Lewis-acid catalysis is effective in intermolecular as well as intramolecular homo-Diels±Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). Co(acac)2, dppe Et2AlCl, (3−6 equiv) ( )n R ( )n 93 R n = 1, 2 92 n 1 1 1 1 2 2 2 R Yield (%) H 78 Me 69 TMS 63 Ph 70 H 64 Me 43 TMS 48 Scheme 3.18 3.5 CATIONIC DIELS±ALDER REACTION The cationic moiety attached to the carbon±carbon double bond is a strong electron-withdrawing group that increases the dienophilic character of the double bond in the Diels±Alder reaction. 2,2-Dimethoxyethylacrylate (94) may be readily converted into the cationic species 95 by the action of Lewis acids [92] (Equation 3.32); the cationic species then undergoes Diels±Alder reaction with a variety of dienes. The type of catalyst markedly affects the reaction yield, stereoselectivity and regioselectivity as shown in Scheme 3.19 and Equation 3.33. Another model cationic species [92] that has been studied is cation 99 which is obtained from 2-oxopropylacrylate 98. By treating compound 98 with equimolecular amounts of trimethylsilyltrifluoromethane sulfonate and methoxytrimethylsilane in the presence of 1,3-cyclohexadiene, a cycloadduct is produced Lewis-Acid-Catalyzed Diels±Alder Reaction 129 O OMe O + TiCl4 O DCM, −78 ⬚C MeOTiCl4 24 h OMe OMe O 94 3:32 95 O O O OMe Cat. + O DCM, −78 ⬚C, 24 h OMe 94 Cat. OMe OMe 3:33 Yield (%) para:meta TiCl4 Me3SiOTf 97:3 >99:< 1 66 78 in 89 % yield (Equation 3.34). It should be noted that the addition of methoxytrimethylsilane is essential for the generation of the allylcation intermediate. O + Lewis acid O OMe MeO 94 ( )n n = 1, 2 DCM, −78 ⬚C, 24 h ( )n ( )n O O O + H O OMe H OMe 97 96 n 1 1 1 1 2 2 Lewis-acid Yield (%) 96:97 TiCl4 Me3SiOTf BF3 OEt2 GaCl3 TiCl4 Me3SiOTf 85 41 21 84 89 83 25:1 34:1 69:1 45:1 100:0 100:0 Scheme 3.19 OMe OMe 130 Outlined Diels±Alder Reactions O O DCM, −45 ⬚C O Me3SiOTf-Me3SiOMe O OMe 10 h 89%; O 98 3.6 O O O endo/exo = >110:1 99 3:34 OUTLINED DIELS±ALDER RECTIONS LiBF4 : a mild Lewis-acid for intramolecular Diels±Alder reactions [93] O PhH, LiBF2 O H r.t., 72 h, 100% H Diels±Alder reactions of 2-bromo-2-cycloalkenones. A convenient approach to doubly cisoid fully conjugated dienone system [94] R1 O O R2 Br + n( ) R3 Br R1 R2 MeCN, SnCl4, r.t. 17−62 h, 75−91% n( ) R3 H PhH, DBU, r.t., 0.6−1.5 h, 84−96% n = 1, 2 R1, R2, R3 = H, Me four dienes: 75−91% R1 O O R2 n( ) H R3 R1 R2 + n( ) R3 Lewis-Acid-Catalyzed Diels±Alder Reaction 131 An asymmetric route to the 5,6-dehydro-4H-1,3-thiazine skeleton via an asymmetric hetero-Diels±Alder reaction [95] Ph S N Me N DCM, Cat., −78 to −20 ⬚C X* + Ph 3 h, 58−95%, de = 50−70% O Me S Ph + N Me N COX* N S Me COX* N Me major X* = CO2Et O Me minor Cat = TiCl4, TiCl2(O-iPr)2, EtAlCl2, Et2AlCl, MgBr2; Yield: 58−90% O X* = N Cat = MgBr2; Yield: 95%, de = 100% O Ph Nickel-catalyzed [2 2 2] (homo-Diels±Alder) and [2 2] cycloadditions of bicyclo[2.2.1]hepta-2,5-dienes [96] X + Ni(COD)2PPh3 ClCH2CH2Cl O X ( )n , Dienophiles: X = CHO, COMe, COt-Bu, CN, SOPh, SO2Ph, O , O N Ph O O Lewis-acid-catalyzed Diels±Alder reaction of 3-phenylthio-2- quinolinones with siloxydiene. Synthesis of the intermediate for dynemicin A core [97] O O MeO2C N SPh PhMe, EtAlCl2, r.t. + SPh N 60−70% OSMT no reaction without catalyst. H MeO2C H O 132 Outlined Diels±Alder Reactions Catalytic asymmetric aza-Diels±Alder reactions using a chiral lanthanide Lewis acid. Enantioselective synthesis of tetrahydroquinoline derivatives using a catalytic amount of a chiral source [98] R3 HO N H R1 H + R3 H R2 R2 DCM, Cat* −15 to 45 ⬚C, 52−90%, ee: 61−91% N OH R1 H R1, = Ph, α-Napht, C6H11 OEt , alkenes: OBu , , , O additives: DPP, DTBP, DTBMP Investigations into the use of niobium and tantalum complexes as Lewis acids [99] R1 R Cat. + 5 − 78% CHO H R H CHO R1 + R H CHO R1 R, R1= H, Me A simple and practical synthesis of ()-2- bromobicyclo [2.2.1]hept-5-ene-2-carboxaldehyde via chiral Lewis-acid catalyzed [4 2] cycloaddition [100] R H (S)-BINOL/Ti(Oi-Pr)4 + CHO DCM, −20 to −78 ⬚C, 0.1−24 h 70−94%, ee: 50−94% O R = Me, Br R endo/ exo = 17:1 Cationic bis(oxazoline) and pyridil-bis(oxazoline) Cu(II) and Zn(II) Lewis-acid catalysts. A comparative study in catalysis of Diels±Alder and aldol reactions [101] O O DCM, Cat* O + N R1 R1+ −78 ⬚C ee: 64−98% O R1 = H, Me Me Me O Cat* 2 M N 2 SbF6 R R 2 Cat* O O N N Ph X X R = t-Bu, M = Cu R = Ph, M = Zn O N R1 O M N M = Cu, Zn The Cu-based catalysts were found to be superior 2 SbF6 Ph Lewis-Acid-Catalyzed Diels±Alder Reaction 133 Exclusively endo-selectivity Lewis-acid catalyzed hetero-Diels±Alder reactions of (E)1-phenylsulfonyl-3-alken-2-ones with vinylethers [102] R 2O O SO2Ph + R1CH=CHOR2 R O SO2Ph DCM, Cat., 15−240 h −50-r.t., 24−97% R1 R endo R = H, Me, i-Pr, Ph; R1 = H, Me, Ph; R2 = Et, i-Bu, Ph Cat = ZnI2, Eu(fod)3, TiCl2(Oi-Pr)2 Chiral Lewis acids supported on silica gel and alumina, and their use as catalysts in Diels±Alder reactions of methacrolein and bromoacrolein [103] Derivatives of (S)-tyrosine were supported on silica gel through the phenolic oxygen atom and treated with BH3 to give Lewis acids able to accelerate the Diels±Alder reactions of methacrolein and bromoacrolein with cyclopentadiene. (S)-Prolinol has been supported on silica gel and alumina and then treated with EtAlCl2 to give a supported catalyst. O Me O H Br H The observed enantioselectivity was zero or very low. Highly selective Lewis-acid-catalyzed Diels±Alder reactions of acyclic (Z)-1,3-dienes [104] ROC X X + PhMe, MeAlCl2, −78 ⬚C 1 h, 54−97% COR X = H, Me, OAc; R = H, NHBz four dienes; six dienophiles; catalyst: MeAlCl2, SnCl4 Lewis-acid-catalyzed asymmetric hetero-Diels±Alder cycloaddition of a 1-thiabuta1,3-diene with chiral N-acryloyl and N-crotonyl oxazolidinone dienophile [105] Ph + Ph S O O N R O N Me2AlCl or TiCl4 9−99% Ph Ph R = H, Me O Ph O DCM, 0 ⬚C, 2 h S O R Ph endo:exo = 99:1 to 61:39 134 Outlined Diels±Alder Reactions Imino Diels±Alder reactions catalyzed by indium trichloride InCl3 . Facile synthesis of quinoline and phenanthridinone derivatives [106] R1 R1 H R3 20 mol% InCl3, r.t. R2 + R2 0.5−0.7 h, 58−95% N NH H H R1 = H, Cl, NO2, OMe; R2 = H, Me, Et, NO2, COOH R3 = H, Me, Cl R3 R R O H H MeCN, InCl3, r.t. + Ph O R 24 h, 60−70% N NH H + NH O Ph H Ph H R = H, Cl, NO2, OMe Methylalumoxane as a highly Lewis-acidic reagent for organic synthesis [107] R1 COR DCM, MAO, 0.5−42 h + + 0 ⬚C to −78 ⬚C, 85−99% COR R = H, Me, OMe; R1 = H, Me Methylalumoxane = MAO = COR R1 R1 Me Al O n Scandium(III) perfluorooctanesulfonate Sc OPf3 : a novel catalyst for the heteroDiels±Alder reaction of aldehydes with non-activated dienes [108] O H R + hexane, 30 mol% Sc(OPf)3 r.t., 24−96 h, 41−98% R = Ph, p-XC6H4 (X = NO2, Cl, Me, OMe, Ph, NO2), -Naphthyl, PhCH2CH2, C6H11, C6H13 O R Lewis-Acid-Catalyzed Diels±Alder Reaction 135 Synthesis of decalin synthons of bioactive terpenoids: Lewis-acid-catalyzed Diels± Alder reactions [109] O O PhMe, 0 ⬚C, AlCl3 + 3.5 h, 60% six dienophiles: 35−80% Enantioselective Diels±Alder reactions between cyclopentadiene and a,b-acetylenic aldehydes catalyzed by a chiral super Lewis acid [110] H O DCM, Cat*, 14−17 h + R −94 to −78 ⬚C, 37−83%, ee: 80−87% CHO R R = TMS, TES, Me2PhSi, Bu3Sn Br N Cat* = B O B[C6H3-3,5(CF3)2]4 2 Dilithium 2,20 -methylenebis(4,6-di-tert-butylphenoxide) as a bidentate Lewis acid in organic synthesis [111] H + PhMe, −78 to −20 ⬚C O 8.5 h, Cat (A, B, C) H + H CHO Cat. A B C O Li Li O t-Bu O t-Bu t-Bu t-Bu A Li Li Endo/Exo 76 81 − t-Bu B Yield (%) 77 50 traces O t-Bu t-Bu 24 19 − O t-Bu CHO Li t-Bu t-Bu C 136 Outlined Diels±Alder Reactions The carbonyl Diels±Alder reaction catalyzed by bismuth(III) chloride [112] R1 CO2Et R R1 CHCl3, BiCl3, 20 ⬚ to 60 ⬚C R2 O + R2 HO O 0.3−24 h, 47−96% R + CO2Et R = H, CO2Et; R1, R2 = H, Me R R2 CO2Et R1 major minor Eu fod3 and SnCl4 -catalyzed heterocycloadditions of o-silylenol ethers deriving from cyclic ketones [113] Ph + O RO MeO Petrol Ether or DCM, 60 or −78 ⬚C 1−60 h, 10−99%, Cat. O Ph MeO O O Ph H + MeO OR Ph H + MeO O OR O exo endo O O H OR abnormal R = Me, SiMe2t-Bu, SiPh2t-Bu, SiMe3; Cat = Eu(fod)3, SnCl4, TiCl4 In the presence of Eu(fod)3 the endo-cycloadduct is the predominant reaction product; in the presence of SnCl4 the abnormal product is predominant Reactivity and diastereoselectivity in the thermal and Lewis-acid-catalyzed Diels± Alder reactions of N-sulphinylphosphoramidates [114] S O + N X O O S P X N Y DCM, SnCl4, −78 ⬚C O 5 min, 41−90% P exo Y X, Y = (EtO)2; (MeO)2; Ph2, O O, O N , Pr O N t-Bu + O O S P X N Y endo Lewis-Acid-Catalyzed Diels±Alder Reaction 137 Lewis-acid-catalyzed Diels±Alder reactions of highly hindered dienophiles [115] O O O + AlMe3/AlCl3 R −20 ⬚C - r.t., 50−91% O R n n n = 1, 2 R = Me, Ph; endo/exo from 2:1 to 7:1 The first enantioselective aza-Diels±Alder reactions of imino dienophiles on use of a chiral zirconium catalyst [116] OH HO OSMT + N R PhMe, Cat.* − 45 OMe ⬚C, N 47−98%, ee = 64−93% R1 H R R1 O R = a-Naphthyl, o -MeC6H4, Ph, Me(OMe)2C6H3, 2-Thienyl, Cy; R1 = H, Me; L = NMI, DMI Br Br L O O Zr O O L Cat* = L = Ligand Br Br A new chiral ligand for the Fe-Lewis-acid catalyzed asymmetric Diels±Alder reaction [117] H DCM, Cat*, −20 ⬚C, 20 h O 68−83%, ee 97% 2,6-di-t-butylpyridine + CHO exo/endo = 49 BF4 Fe P(C6F5)2 L = acrolein, benzaldheyde Cat* = (C6F5)2P O L O Ph Ph three aldehydes: three dienes 138 References Aluminum trisphenoxide polymer as a Lewis-acidic solid catalyst [118] H PhMe, Cat. + −78 ⬚C or r.t., 99% O H COH endo/exo = 3.5 four dienophiles, three dienes: n n Ph Cat = PhO Al O n Ph Ph O Ph Ph Ph Ph Ph O Al O Ph Ph O Ph n REFERENCES 1. 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The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 4 Diels±Alder Reaction Facilitated by Special Physical and Chemical Methods The Diels±Alder reaction is the most widely used carbon±carbon, carbon± heteroatom and heteroatom±heteroatom bond-forming reaction for the construction of six-membered rings; therefore it is not surprising that many methods have been used to accelerate the reaction and to improve its selectivity. Chapters 2, 3 and 5 illustrate the effects of temperature, Lewis acids and pressure, respectively; this chapter provides a survey of other physical and chemical methods by which the Diels±Alder reaction can be profitably carried out. A compendium of these special methods was reviewed by Pindur in 1993 [1]. 4.1 SOLID-PHASE DIELS±ALDER REACTION Solid-phase chemistry is an efficient synthetic tool that, compared with solution-phase chemistry, simplifies the work-up of the reaction, allows the process to be driven to completion by using excess of reagents, and can be automatized [2a]. In recent years, many studies have been devoted to developing both surface-mediated and resin-supported synthesis. Today the solid-phase approach is not limited to peptides and oligonucleotides but is also used to synthesize molecules of lower molecular weight. The Diels±Alder reaction on solid support was first performed 20 years ago and is now a consolidated procedure [2b]. 4.1.1 Inorganic Solid-Surface-Promoted Diels±Alder Reaction Porous surfaces of inorganic solids such as clays, silica gel, alumina and zeolites are the commonest systems used as catalysts in Diels±Alder reactions. Two classes of clays are known [3]: (i) cationic clays (or clay minerals) that have negatively charged alumino-silicate layers balanced by small cations in the interlayer space (e.g. K-10 montmorillonite) and (ii) anionic clays which have positively charged brucite-type metal hydroxide layers balanced by anions and water molecules located interstitially (e.g. hydrotalcite, Mg6 Al2 OH16 CO3 4H2 O. 144 Solid-Phase Diels±Alder Reaction It is believed that clay minerals promote organic reactions via an acid catalysis [2a]. They are often activated by doping with transition metals to enrich the number of Lewis-acid sites by cationic exchange [4]. Alternative radical pathways have also been proposed [5] in agreement with the observation that clay-catalyzed Diels±Alder reactions are accelerated in the presence of radical sources [6]. Montmorillonite K-10 doped with Fe(III) efficiently catalyzes the Diels±Alder reaction of cyclopentadiene (1) with methyl vinyl ketone at room temperature [7] (Table 4.1). In water the diastereoselectivity is higher than in organic media; in the absence of clay the cycloaddition proceeds at a much slower rate. By using unactivated K-10 montmorillonite in the absence of solvent, the endo±exo selectivity of the cycloadditions of acrolein and methyl vinyl ketone with cyclopentadiene and cyclohexadiene is low [8] (Table 4.2, entry 3), while highly reactive dienophiles such as 1,4-benzoquinone and N-phenyl Table 4.1 Diels±Alder reactions of cyclopentadiene (1) with methyl vinyl ketone catalyzed by Fe(II)-K-10 montmorillonite in various solvents O O K10-Fe(II) + + 20 ⬚C, 3 h 1 (endo ) Medium endo/exo H2 O CH2 Cl2 EtOH 19:1 9:1 14:1 O (exo ) Yield (%) 95 97 95 Table 4.2 Solvent-free Diels±Alder reactions in the presence of unactivated K-10 montmorillonite at 0 8C Entry Dienea 1 2 3 4 5 6 7 8 CP CP CP CP CH CH CH CH a Dienophileb t(h) BQ NPM MVK AC BQ NPM MVK AC 5 14 3 3c 8 6 2d 2d endo/exo Yield (%) >99 >99 10 5 >99 >99 19 11 70 98 95 78 64 86 78 50 CP cyclopentadiene, CH 1,3-cyclohexadiene; BQ 1,4-benzoquinone, NPM N-phenyl maleimide, MVK methyl vinyl ketone, AC acrolein; c at 25 8C;[ d at 25 8C b Diels±Alder Reaction Facilitated by Physical and Chemical Methods 145 maleimide give exclusively endo addition (Table 4.2). A parallel study carried out in the presence of alumina revealed that reactions on the surface of K-10 montmorillonite are faster and give higher yields and that the beneficial effect of alumina is dependent on its degree of activation. The investigation on the use of K-10 montmorillonite under free solvent conditions was then extended to inner ring dienes such as furan and its 2,5dimethyl derivative [9] (Table 4.3). The cycloadditions generally proceed slowly, and Zn(II)-doped clay and microwave irradiation were used to accelerate the reactions. The reaction with maleic anhydride preferentially affords the thermodynamically favored exo adduct. Clay-catalyzed asymmetric Diels±Alder reactions were investigated by using chiral acrylates [10]. Zn(II)- and Ti(IV)-K-10 montmorillonite, calcined at 55 8C, did not efficiently catalyze the cycloadditions of cyclopentadiene (1) with acrylates that incorporate large-size chiral auxiliaries such as cis-3neopentoxyisobornyl acrylate (2) and (±)-menthyl acrylate (3, R H) (Figure 4.1). This result was probably due to diffusion problems. Table 4.3 Solvent-free Diels±Alder reactions in the presence of unactivated K-10 montmorillonite R O K-10 Mont. + R X 0 H H H H Me Me NPh NPh O O NPh NPh 24 0.25 3 0.03 1.5 0.17 c R T (8C) or MWa t (h) b 0 MWb 0 MWc 0 MWb O 2 Figure 4.1 X H R H O (exo ) endo/exo Yield (%) 1.3:1 1.5:1 1:3 1:3 2.3:1 2.3:1 85 80 36 16 77 100 Microwave irradiation; 150 W; 300 W O O H X O (endo ) X O O R O + ⬚C O R a O RH H O R H O O O O O 3 4 O 146 Solid-Phase Diels±Alder Reaction Table 4.4 Diels±Alder reactions of (R)-O-acryloylpantolactone (4 ) with cyclopentadiene (1) in methylene chloride Catalyst T (8C) none TiCl4 EtAlCl2 Zn-120 Fe-550 Ti-550 a 20 10 10 20 20 20 1/4a t(h) endo/exo d.e. (%) Yield (%) 6:1 1.5:1 1.5:1 5:1 5:1 3:1 24 0.5 1 24 24 2 75:25 99:1 99:1 93:7 98:2 90:10 6 92 42 43 39 43 100 100 94 97 98 94 Molar ratio Good results were obtained with (R)-O-acryloylpantolactone (4) in which the dienophile was incorporated with a smaller chiral auxiliary. Some results are reported in Table 4.4, where the cycloadditions catalyzed by Zn(II)-, Fe(II)- and Ti(IV)-K-10 exchanged montmorillonite calcined at 120 8C and 550 8C are compared with those that were not catalyzed and with TiCl4 - and EtAlCl2 catalyzed reactions. Among the metal-clays activated, the Ti(IV)-K-10 was the best catalyst with high conversion and acceptable enantioselectivity obtained after 2 h. Silica gel [11] or alumina [11a, 12] alone, or silica and alumina together modified by Lewis-acid treatment [13] and zeolites [14], have been widely used as catalysts in Diels±Alder reactions, and these solids have also been tested as catalysts in asymmetric Diels±Alder reactions [12,13b,14]. Activated silica gel and alumina at 140 8C were used [15] to catalyze the asymmetric cycloaddition of (±)-menthyl-N-acetyl-a,b-dehydroalaninate (3) (R NHCOMe) with cyclopentadiene in the key step for synthesizing optically active cycloaliphatic a-amino acids. When the reactions were carried out in the absence of solvent, a higher conversion was obtained. Some results are reported in Table 4.5 and compared with those obtained by using silica and alumina modified by treatment with Lewis acids. Silica gel gives a reasonable percentage of conversion after 24 h with complete diastereofacial selectivity in exo addition. Commercial chromatography silica gel promotes effectual Diels±Alder cycloaddition of optically active pyrone lactate ester (5) with benzyl vinyl ether (6), affording the endo adduct 7 in an approximately 4:1 mixture of diastereoisomers [16] (Equation 4.1). H O O H CO2Me O O Bn + SiO2, 25 ⬚C PhMe, 60% O 5 O 6 d.e. 58% O O O O H 7 Bn CO2Me 4:1 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 147 Table 4.5 Solvent-free Diels±Alder reactions of ( )-menthyl N-acetyla,b-dehydroalaninate (3, R NHCOMe) with cyclopentadiene (1) at 25 8C Catalyst C (%)a endo/exo d.e. (endo) d.e. (exo) 88 55 49 45 29:71 36:64 33:67 39:61 70:30 69:31 80:20 75:25 >97:3 >97:3 >97:3 >97:3 SiO2 -140 Al2 O3 -140 SiO2 Et2 AlCl SiO2 TiCl4 a b Conversion after 24 h Related to ester group Oxazoborolidinone 8 is an example of catalyst supported on silica gel. It is prepared by immobilizing the N-tosyl-O-allyl-(S)-tyrosine with mercaptopropyl silica and treatment with BF3 and has been used to catalyze the Diels±Alder reaction of methacrolein with cyclopentadiene [17] (Equation 4.2). The cycloaddition occurs with good diastereoselectivity but with low enantioselectivity. Cat.*, 20 ⬚C, 20 h CHO + Conv.69%, exo/endo = 92/8 CHO ee = 7% 4:2 O Cat.* = O OMe O Si O (CH2)3-S-(CH2)3 O 8 N B H Ts Better enantiomeric excess was obtained by using (±)-menthol-aluminum Lewis acids supported on silica gel and alumina through the aluminum atom [17]. Pagni and coworkers [18] have conducted in-depth investigations on the cycloadditions of cyclopentadiene with methyl acrylate on alumina of varing activity (200 8, 300 8, 400 8, 800 8) showing that the diastereoselectivity of the reaction is markedly dependent on the activity of the alumina. The exo/endo ratio goes up significantly on 400 8-Al2 O3 having a value of 52 for 10:1 w/w ratio of Al2 O3 to reactants. Unexpectedly the exo/endo ratio dropped to 0.93 when the reaction was run on 800 8-Al2 O3 . These results were explained on the basis of stability and epimerization of adducts. Catalysis of Diels±Alder reaction by zeolites is predominantly physical rather than chemical in nature [19]. The reactants are concentrated internally in cavities 148 Solid-Phase Diels±Alder Reaction of material, which provides two advantages: (i) by increasing the reactant concentration inside the zeolite pores, the rate of bimolecular reaction such as the Diels±Alder cycloaddition is enhanced; in this regard, the effect of zeolites is comparable to that obtained with the use of high pressure; and (ii) the geometry of the zeolite cavities influences the regio- and stereoselectivity of the reaction. The nature of the zeolites therefore has a great influence on the reactivity and selectivity of the process. The use of zeolites is particularly advantageous for self-Diels±Alder reactions of gaseous dienes because it reduces the polymerization of the reactant. An example is the cyclodimerization of 1,3-butadiene to 4-vinylcyclohexene [20a] carried out at 250 8C with satisfactory conversion when non-acidic zeolites, such as large-pore zeolites Na-ZSM-20, Na-b and Na-Y, are used. The ability of zeolites to control the regioselectivity of Diels±Alder reaction has been investigated for the cycloaddition of isoprene with various dienophiles [20b]. Some results are reported in Table 4.6. All the zeolites tested afforded high regioselectivity but the reaction yield was generally low and depended on the zeolite as well as on the dienophile. Good yields and high diastereoselectivities were obtained by using zeolites in combination with Lewis-acid catalyst [21]. Table 4.7 illustrates some examples of Diels±Alder reactions of cyclopentadiene, cyclohexadiene and furan with methyl acrylate. Na-Y and Ce-Y zeolites gave excellent results for the cycloadditions of carbocyclic dienes, and combining these zeolites with anhydrous ZnBr2 further enhanced the endo diastereoselectivity of the reaction. An exception is the cycloaddition of furan that occurred considerably faster and with better yield, in comparison with the classic procedure [22], when performed in the presence of sole zeolites. Table 4.6 Diels±Alder reactions catalyzed by zeolites O R O Zeolite, DCM R1 O R Rfx, 24 h 9 R R1 Y-152 9/10 Me Me OMe a H 95:5 Br 94:6 H 97:3 yield(%) Yielda 55 40 48 Y-45 9/10 Yielda 94:6 93:7 97:3 69 53 31 ZSM-5 9/10 98:2 87:13 100:0 R + R1 R1 + 10 Mordenite Yielda 9/10 100 23 11 97:3 85:15 96:4 Beta Yielda 9/10 Yielda 91 34 33 97:3 94:6 99:1 62 39 100 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 149 Table 4.7 Diels±Alder reactions of carbo-and heterocyclic dienes with methyl acrylate catalyzed by zeolites and ZnBr2 doped zeolites O X X Catalyst, DCM + OMe 0 ⬚C, 1−3 h MeO Catalyst X Na-Y NaY=ZnBr2 Ce-Y CeY=ZnBr2 NaY=ZnBr2 CeY=ZnBr2 Ce-Y CeY=ZnBr2 CH2 CH2 CH2 CH2 CH2 2 CH2 2 O O a 4.1.2 O endo (%) Yield (%) 90 96 90 96 85 90 40±50a 40a 96 98 96 100 95 100 70 70 Reaction time 24 h Diels±Alder Reaction Using Resin-Anchored Reagents A solid-phase Diels±Alder reaction that uses polymer-supported reagents has recently attracted considerable attention and its use is expanding rapidly. Intramolecular Diels±Alder reactions of amino acid-derivative trienes 13 (Scheme 4.1) onto solid support have been used for rapid stereoselective synthesis of heterocyclic compounds for high throughput drug screening [23]. The synthesis starts from phosphono-acetyl-Wang resin 11 which is converted to secondary amines 12 and then to resin-bound trienes 13 by acylation reaction. Trienes 13 cyclize at room temperature giving predominant trans-fused bicyclic adducts 14. Trienes 15, containing a furyl as diene, were prepared similarly and their cycloadditions also proceeded at room temperature to give 1,4-epoxyisohydroindolines 16 which were derived from an endo transition state pathway. The resin was cleavaged with TFA-DCM. The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels± Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels±Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 150 Solid-Phase Diels±Alder Reaction i -BuO2C OEt COO EtO P O NH 11 N-methylmorpholine R2 DCM COO N O 13 1. r.t., 30−72 h DCM 2. TFA 12 R3 R1 R2 R1 R1, R2 = Bn, i -Pr Wang resin O COO R1 R2 O H N O O COCl COOH 1. r.t. R R3 60−148 h 1 DCM O N R2 2. TFA O O 16 R1 COO R2 H COOH N O H R3 15 14 Scheme 4.1 R CHO O 17 R = H, Me + BnNH2 + 18 BnNC E1 + COOH E2 19 E1, E2 = H, CO2Et, CONHBn 20 O R r.t., 36 h MeOH 72−89% E1 Bn O H N N O H E2 O Bn 21 Scheme 4.2 Bn R E 1 E2 N N O Bn 22 isomer ratio = 86−92/14−8 O Diels±Alder Reaction Facilitated by Physical and Chemical Methods 151 The solid-phase synthesis carried out on acid labile Argo Gel-Rink resin, by using the resin-bound amine 23, gives cycloadducts 24 with similar results [24] (Scheme 4.3). Another efficient approach to these tricyclic nitrogen heterocycles consists of treating the immobilized amine 23 with excess of furylaldehydes 25 in trimethyl orthoformate [25] (TMOF). Reduction of the resulting imine with NaBH4 furnishes the furylamines 26 which, in the presence of maleic anhydride, gives the cycloadduct 27 via an initial N-acylation followed by an intramolecular Diels±Alder reaction. The resin-bound carboxylic acid 27 was used as a key intermediate for preparing a number of derivatives. O O NH2 + 17 + 19 + 20 N 1. MeOH, DCM 2. TFA 88−95% R E 1 H Bn E2 N H N O NH2 23 (R1, R2 = H, Me) R1 O N H 24 O isomer ratio 77;91/23;9 R2 1. TMOF 2. NaBH4 O O 25 CHO R2 R2 H N O COOH O O R1 R1 O Py, r.t. 26 O H N O N O 27 Scheme 4.3 A novel and versatile method for preparing polymer-supported reactive dienes was recently developed by Smith [26]. PS-DES (polystyrene diethylsilane) resin 28 treated with trifluoromethanesulfonic acid was converted to a polymer-supported silyl triflate 29 and then functionalized with enolizable a,bunsaturated aldehydes and ketones to form silyloxydienes 30 and 31 (Scheme 4.4). These reactive dienes were then trapped with dienophiles and the Diels± Alder adducts were electrophilically cleaved with a solution of TFA. 152 Solid-Phase Diels±Alder Reaction Et (CH2)4 Si Et Et CF3SO3H (CH2)4 Si DCM H 28 29 O O R1 R2 R3 R3 R3 Et Et (CH2)4 Si O R2 Et Et (CH2)4 Si O R1 R1 31 R2 O R3 31−97% O O O N R 18−99% R1 H R2 30 Et OSO2CF3 O R3 OH O O R1 O N R R1 R2 R3 O R2 O O R1, R2, R3 = H, Me, Et, Ar Scheme 4.4 A cross-coupling reactions of terminal alkynes with terminal alkenes 32 supported on Merrifield-resin (Scheme 4.5) in the presence of Grubs' ruthenium initiator [Cl2 PCy3 2 Ru CHPh] provided efficient access to supported 1,3dienes 33 which were transformed into octahydrobenzazepinones 34 via MeAlCl2 catalyzed Diels±Alder reaction [27]. To generate molecular libraries, a series of 5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs were prepared via a stereospecific Diels±Alder reaction by reacting Wang-resin-bound diene 35 with a variety of dienophiles [28]. After removing the solid support with a strong acid, adducts 36 were isolated; examples of reactions that have furnished the best yields are reported in Scheme 4.6. Diels±Alder Reaction Facilitated by Physical and Chemical Methods 153 O O RCH2C Cat., DCM 45 ⬚C, 24 h O O CH R1 R O 32 O MeAlCl2, DCM −35 ⬚C, 18 h 33 R O R1 O O N R2 O 2. Et3N, DCM 60 ⬚C, 24 h R1 R O 1. Me3Al, DCM r.t. 0.5 h. R R2 R2NH2, DCM r.t., 12h H N R1 34 R = (CH2)4Me, CH2OH, OCH2Ph, NMeCbz R1 = H, Me R2 = Me, (CH2)nPh n = 1, 2, 3 Scheme 4.5 O R O O R1MgX O Cl N O N O + N H R R R1 35 O R1 N O R R1 N Y Y Y Y Y O R Y O 36 R R1 Dienophile Yield (%) p-Me-C6H4 p-Me-C6H4 NPMa 52 m-MeO-C6H4 p-Me-C6H4 NPMa 61 p-Me-C6H4 p-Me-C6H4 (EtOCON=)2 83 a NPM = N-phenylmaleimide. Scheme 4.6 65 ⬚C, 12h THF 154 4.2 Ultrasound-Assisted Diels±Alder Reaction ULTRASOUND-ASSISTED DIELS±ALDER REACTION The use of ultrasonic (US) radiation (typical range 20 to 850 kHz) to accelerate Diels±Alder reactions is undergoing continuous expansion. There is a parallelism between the ultrasonic and high pressure-assisted reactions. Ultrasonic radiations induce cavitation, that is, the formation and the collapse of microbubbles inside the liquid phase which is accompanied by the local generation of high temperature and high pressure [29]. Snyder and coworkers [30] published the first ultrasound-assisted Diels±Alder reactions that involved the cycloadditions of o-quinone 37 with appropriate dienes 38 to synthesize abietanoid diterpenes A±C (Scheme 4.7) isolated from the traditional Chinese medicine, Dan Shen, prepared from the roots of Salvia miltiorrhiza Bunge. O O O O + O 1. US R1 R2 37 O 2. DDQ R1 R3 R2 38 R1, R2, R3 = see Table 4.8 R3 O O O A; B; C O O O O O O HO R A R = Me R = CO2Me R = CH2OH R=H O B R R1 C R = R1 = Me R = Me, R1 = OH Scheme 4.7 The thermal instability of 37 reduces its applicability with poorly reactive dienes such as vinylcyclohexene and its derivatives 38, unless high pressure (HP) is employed. Ultrasound is not only effective in promoting the cycloaddition of 37 with 38, but sometimes also improves the regioselectivity. Some data are illustrated in Table 4.8 and compared with cycloadditions in refluxing benzene and under high pressure. The reactions of 37 with reactive dienes such as cyclopentadiene and 1-(trimethylsiloxy)-1,3-butadiene give a good yield of type D adducts under mild conditions, while with less reactive dienes, such as isoprene and butadiene, poor results are obtained. Ultrasound irradiation is particularly beneficial for Diels±Alder reactions of unactivated azadienes because the reaction can be carried out under mild conditions. Diels±Alder Reaction Facilitated by Physical and Chemical Methods Table 4.8 o-Quinone ultrasound-assisted Diels±Alder reactions O O + O 37 a b c d e f g O O O 1 2 3 4 5 6 7 8 9 10 11 155 1. US R1 O 2. DDQ R2 + O R3 38 R1 R2 R3 H H H H H H H H H O-CH2 -O OSMDTB H H H Me O-COPh O-CMe2 OCH2 O- CH2 2 -O CO2 Me OSMDTB H Me SiMe3 Me CO2 Me Me O Me Me Me Me D E Yield (%) D/E PhHa HPb 45 11 18 53 67 62 18 75 15 73 USc PhH HP 65 56 57 76 76d 72 f 65 66 71g 66 73h 6 2 10 0.3 1.2 1 1 US 3.5 20 0.3 0.2 3.3 2.5e 4f 2.5 8 8 12g 7 5 30h Reflux, 6±12 h; 10±11 kbar, 0.75±2 h; Neat, 45 8C, 2 h; At 8 8C; In MeOH, 0 8C, 8 h, yield 50%, A/B 5.5; At 25 8C; in MeOH, 3 h, yield 59 %, A/B 10; In MeOH, 45 8C, 1.5 h; h: In MeOH, 35 8C, 1 h The Diels±Alder reaction between 1-dimethylamino-4-methyl-1-azadiene 39 and 5-hydroxynaphthoquinone 40 was investigated by Luche, Jenner and coworkers [31] in order to obtain some functionalized derivatives of naturally occurring 4-methylated-1-azaanthraquinones. The reactions were performed under sonochemical, thermal and HP conditions in solution and neat conditions. Some results are illustrated in Scheme 4.8. The primary adduct 41 was not isolated due to a rapid elimination of dimethylamine, and the adduct 42 was obtained as a single regioisomer. Ultrasonic irradiation in PhMe accelerated the Diels±Alder reaction but produced 30 % aminoquinones 43 which is the result of an addition-oxidation of dimethylamine to 40. Unlike in the Diels± Alder reactions of o-quinone 37 with vinylcyclohexenes 38, methanol and neat reaction conditions were not a good reaction medium for this sonochemical cycloaddition. The study was enlarged to include azanaphthoquinones as dienophiles. 156 Ultrasound-Assisted Diels±Alder Reaction O O NMe2 O r.t. r.t. NHMe2 N OH O 40 OH O 43 OH O 41 N NMe2 39 NMe2 - NHMe2 O N OH O 42 H Medium Conditions t(h) 42(%) 43(%) PhMe PhMe PhMe MeOH MeOH Neat Neat US Ð HP US Ð US Ð 6 24 6 6 6 6 6 52 48 48 14 15 15 14 30 traces traces traces traces traces traces Scheme 4.8 Spanish researchers [32] also noted a considerable improvement upon sonication of Diels±Alder reactions of 1-dimethylamino-3-methyl-1-azadiene 44 with a variety of electron-deficient dienophiles by using diene as solvent or in acetonitrile (Scheme 4.9). Ultrasound irradiation which allows mild reaction conditions gave good to excellent yields. The sonochemical effect, the importance of solvent and the mechanism of US-assisted Diels±Alder reaction were recently critically investigated [33±35]. Caulier and Reisse [33] studied the influence of US on the yield and diastereoselectivity of the reaction between cyclopentadiene and methyl vinyl ketone in various organic solvents. Yield and endo/exo diastereoselectivity increased with US in halogenated solvents (CHCl3 , CH2 Cl2 , CH2 Br2 ) whereas they were not affected in non-halogenated solvents (CH3 OH, PhMe). The authors give evidence that the cycloaddition is not affected by US, but US promotes the in situ generation of hydrogen halide which acts as catalyst. The observed sonochemical effect would be indirect and this would also occur in other cases described in the literature [36]. In many cases the US acts by mechanical effects (the same result could be obtained by very efficient stirring) or by generating radicals or molecules that act as catalysts. Diels±Alder Reaction Facilitated by Physical and Chemical Methods N CO2Me N H B 99% CO2Me G 47% Me2 44 F CO2Me 95% O 50% O C 80% N NMe2 N NMe2 60% A NMe2 N O NMe2 CO2Me N CN 157 N O D O 67% 35% E CO2Me N NMe2 N O N COMe NMe2 A = Acrylonitrile; B = Benzoquinone; C = Naphthoquinone; D = 5,8-Quinolinequinone; E = Methyl vinyl ketone; F = Dimethyl acetylene dicarboxylate; G = Methyl acrylate; H = Dimethyl fumarate Scheme 4.9 Luche and coworkers [34] investigated the mechanistic aspects of Diels±Alder reactions of anthracene with either 1,4-benzoquinone or maleic anhydride. The cycloaddition of anthracene with maleic anhydride in DCM is slow under US irradiation in the presence or absence of 5 % tris ( p-bromophenyl) aminium hexachloroantimonate (the classical Bauld monoelectronic oxidant, TBPA), whereas the Diels±Alder reaction of 1,4-benzoquinone with anthracene in DCM under US irradiation at 80 8C is slow in the absence of 5 % TBPA but proceeds very quickly and with high yield at 25 8C in the presence of TBPA. This last cycloaddition is also strongly accelerated when carried out under stirring solely at 0 8C with 1 % FeCl3 . The US-promoted Diels±Alder reaction in the presence of TBPA has been justified by hypothesizing a mechanism via radical-cation of diene, which is operative if the electronic affinity of dienophile is not too weak. The mechanism of cycloaddition reaction of maleic anhydride with anthracene promoted by US irradiation has been the subject of many controversies [32, 37]. Recent work of Da Cunha and Garrigues [35] shows that the reaction proceeds in toluene solution in the 60±85 8C temperature range in 6±3 h, 158 Microwave-Assisted Diels±Alder Reaction respectively, with high yields (80±88 %) under US irradiation, and that the presence of TBPA does not affect the course of the reaction. Based on these findings the mechanism is postulated to be concerted, excluding any electronic effect. 4.3 MICROWAVE-ASSISTED DIELS±ALDER REACTION Microwave-assisted Diels±Alder reactions have been performed in solvents [38, 39], in free solvent conditions [38c, 40], in solid phase [39, 41] and in the presence of Lewis acids [38c]. Sometimes some of these reaction conditions were combined. French researchers [38c] have investigated the hetero-Diels±Alder reaction of methylglyoxylate and glyoxal monoacetal with 2-methyl-1,3-pentadiene in a microwave oven under various reaction conditions (Table 4.9). The microwave (MW) irradiation does not affect the diastereoisomeric ratio of adducts (trans/cis 70:30) but dramatically reduces the reaction time. The glyoxal monoacetal, for instance, gives 82 % adducts after 5 minutes when submitted to irradiation with an incident power (IP) of 600 W in PhH and in the presence of ZnCl2 (Table 4.9, entry 1), while no reaction occurs if carried out for 4 h at 140 8C in sole PhH. Similarly, methylgloxylate in water at 140 8C gives 82 % adducts after 3 h, whereas microwave irradiation reduces the reaction time to 8 minutes (Table 4.9, entry 5). Table 4.9 Diels±Alder reactions of glyoxal derivatives promoted by microwaves under different experimental conditions O + H O R R Entry R Solvent Cat. MW (IP.W) 1 2 3 4 5 PhH, ZnCl2 H2 O neat neat H2 O 600 600 600 72 72 CH OMe2 CH OMe2 CH OMe2 CO2 Me CO2 Me O + R t (min) 5 15 15 10 8 Yield (%) 82 76 54 96 80 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 159 A great acceleration was also observed in the cycloadditions of alkylidene derivatives of 5-iminopyrazoles with nitroalkenes, as electron-poor dienophiles, under MW-irradiation in solvent-free conditions [40c]. Some results are illustrated in Scheme 4.10. All the reactions took place with loss of HNO2 and/or NHMe2 after the cycloaddition, inducing aromatization of the final product. Ph N N Et C6H4-p -OMe N NO2 140 ⬚C, 7 min 285 W, 53% Ph S NO2 N N Et N S NO2 N 13 ⬚C, 5 min 240 W, 84% - NHMe2 N Et N Ph N NO2 R N Ph 140 ⬚C, 10 m 285 W, 32% R =p -MeO-C6H4, NMe2 N N R N Et R =p -MeO-C6H4 Scheme 4.10 Diels±Alder reactions of vinylpyrazoles 45 and 46 only occur with highly reactive dienophiles under severe conditions (8±10 atm, 120±140 8C, several days). MW irradiation in solvent-free conditions also has a beneficial effect [40b] on the reaction time (Scheme 4.11). The indazole 48, present in large amounts in the cycloaddition of 45 with dimethylacetylenedicarboxylate, is the result of an ene reaction of primary Diels±Alder adduct with a second molecule of dienophile followed by two [1,3]-sigmatropic hydrogen shifts [42]. The MWassisted cycloaddition of 46 with the poorly reactive dienophile ethylphenylpropiolate (Scheme 4.11) is significant; under the classical thermal reaction conditions (140 8C, 6 d) only polymerization or decomposition products were detected. 160 Microwave-Assisted Diels±Alder Reaction CO2Me MeO2C N MeO2C C C CO2Me N Ph 45 N CO2Me N Ph CO2Me 8−10 atm 1. DCM, 150 2. MW, 780 W, 130 ⬚C, 6 min CO2Me 48 47 + 48 (18 %) 47 (10 %) + 48 (62%) Ph C C CO2Me N Products (Yield %) ⬚C, Ph N Ph 47 Reaction conditions N + CO2Et N N N Ph Ph 46 Reaction conditions 1. 140 ⬚C, 6 d 2. MW, 180 W, 180 ⬚C, 15 min CO2Et 49 Product (Yield %) 0 19 Scheme 4.11 The Diels±Alder reaction of anthracene and maleic anhydride gives 90 % adduct in refluxing dioxane for 60 h [43]. MW irradiation of free-solvent reaction in a commercial microwave oven (2450 MHz) gives the same yield, but the reaction time is reduced to 3 minutes [40a]. The free-solvent reaction was also investigated by using graphite powder as support [39a]: a continuous MW irradiation with an IP of 120 W during 1 minute gave traces of adduct, but with 30 W and a sequential irradiation (irradiation with `battlements'), the adduct was isolated with 75 % yield. This and other MW-assisted Diels±Alder reactions supported on graphite are illustrated in Table 4.10. Graphite is responsible for a high-temperature gradient leading to increased reaction rates when compared with conventional procedures which use a solvent. The same process was applied to cycloadditions involving carbonyl derivatives as dienophiles and 2,3dimethyl-1,3-butadiene as diene [39b] (Scheme 4.12). The cycloadditions were Diels±Alder Reaction Facilitated by Physical and Chemical Methods 161 Table 4.10 Microwave-assisted Diels±Alder reactions supported on graphite Reagents a Tmax (8C) t(min) MW (IP) Yield (%) 370 155 130 e 1 13 13 1 10 120 30 30 30 92 75 97 50 b A DEF A MAc A DADd 44 DAD a b c d e Anthracene; Diethylfumarate; Maleic anhydride; Dimethyl acetylenedicarboxylate; Not indicated dramatically accelerated with respect to conventional heating conditions, and the absorption of the reagents on graphite allowed the reactions to be carried out in an open reactor. O CO2Et MW [C]a, IP = 30 W O 165 ⬚C, 10X1 min H CO2Et 87% O H O COOH O COOH EtO2C [C]a, MW IP = 60 W 249 ⬚C, 10X1 min 54% a [C]a, CO2Et MW IP = 30 W 165 ⬚C, 20X1 min 75% O CO2Et CO2Et Supported on graphite. Scheme 4.12 A broad study on the MW-assisted Diels±Alder reactions of 2H-pyran2-ones 50 and 51 with 1,4-naphthoquinone 52 and N-phenylmaleimide 53 (Equations 4.3) supported on silica-gel, K-10 montmorillonite, fitrol and alumina was carried out by Samant and colleagues [41]. 162 Microwave-Assisted Diels±Alder Reaction O O R1 O 52 R2 O R1 O 4:3 R1 O O Ph R2 O 50 R1 = R2 = p OMe-C6H4 51 R1 = pOMe-C6H4, R2 = Me N O N Ph O R2 N O Ph O 53 The results of reactions with and without MW irradiation are reported in Table 4.11. The reaction yields are comparable, but the reaction times of the irradiated reactions are considerably reduced. The alumina does not give acceptable results. The same reactions were carried out in nitrobenzene as solvent and under free-solvent conditions with and without MW irradiation. The results are reported in Table 4.12. In this case too, the only significant difference is the reaction time, so that the authors [41] concluded that MW-promoted reactions proceed like the thermal reactions except for a much higher reaction rate. Table 4.11 Diels±Alder reactions of 50 and 51 with 52 and 53 in the presence of a solid support Reagents Support 50 52 51 52 50 53 51 53 50 52 51 52 50 53 51 53 50 52 51 52 50 53 51 53 SiO2 SiO2 SiO2 SiO2 K-10 K-10 K-10 K-10 Fitrol Fitrol Fitrol Fitrol a b c d MWa (Yield %) 73 68 68 68 65 66 67 68 69 70 72 73 With MW, 4 min, HPL 80 % power level; Without MW, 4 h; At 120 8C; At 140 8C NO-MWb (Yield %) 70c 76c 68c 70c 66d 69d 66d 68d 67c 69c 68c 69c Diels±Alder Reaction Facilitated by Physical and Chemical Methods 163 Table 4.12 Diels±Alder reactions of 50 and 51 with 52 and 53 under various conditions Free solvent Yield (%) Reagents 50 51 50 51 a b 52 52 53 53 Nitrobenzene Yield (%) MWa NO-MWb MWa NO-MWb 53 51 49 50 48 69 55 58 76 74 71 70 82 74 65 61 With MW, 4 min, HPL 80 % power level; Without MW, 4 h, 210 8C An example of intramolecular MW-assisted Diels±Alder reaction is illustrated in Equation 4.4. O O 1. SiO2/H2O MW, 5 min, 64% O O OH 2. TBSCl, 75% O O + H OSBT 54 55 4:4 TBSO H 56 The hemiacetal 54 adsorbed on water-saturated silica gel gives, by MW irradiation, a 1:1 mixture of cycloadducts isolated as silyl derivatives 55 and 56. The water is probably necessary for the success of the reaction because (i) it is an efficient generator of heat in the MW process, (ii) it accelerates the cycloaddition by hydrophobic effect, and (iii) it facilitates the hemiacetal± hydroxyketone equilibrium which furnishes the dienophile moiety for the cycloaddition [42]. 4.4 PHOTO-INDUCED DIELS±ALDER REACTION Photo-induced Diels±Alder reaction occurs either by direct photo activation of a diene or dienophile or by irradiation of a photosensitizer (Rose Bengal, Methylene Blue, hematoporphyrin, tetraphenylporphyrin) that interacts with diene or dienophile. These processes produce an electronically excited reagent (energy transfer) or a radical cation (electron transfer) or a radical (hydrogen abstraction) that is subsequently trapped by the other reagent. The single-electron transfer from one excited component to the other component acceptor, as the critical step prior to cycloaddition of photo-induced Diels±Alder reactions, has been demonstrated [43] for the reaction of anthracene with maleic anhydride and various maleimides carried out in chloroform under irradiation by a medium-pressure mercury lamp (500 W). The (singlet) excited anthracene (1 AN ), generated by the actinic light, is quenched by dienophile 164 Photo-Induced Diels±Alder Reaction (DP) and leads (Equation 4.5) to the formation of an anthracene cation radical as a result of the single-electron transfer process. The resulting ion-radical pair [AN , DP is the critical intermediate that subsequently evolves to cycloadduct (AD). 1 + AN DP 4:5 AD AN , DP The thermal reaction of cyclopentadiene (1) with maleic anhydride gives 98 % kinetically favoured endo adduct, unless the mixture is heated for a long time [44]. Under photolysis conditions and in the presence of triethylamine in dry ethanol, a reversed selectivity was found [45] (Scheme 4.13). O H + O H O O + O O O H H O O Conditions endo/exo Et2O, r.t., very fast EtOH, Et3N, hν (300 nm), r.t., 6 h O 98:2 2:98 O OH O O H H O H Me hν, Et3N (5 %) Yield : 64% H O H H O H H O HO hν, Et3N (50%) Yield : 81% hν, Et3N (20 %) Yield : 70% hν, Et3N (5%) Yield : 90% Scheme 4.13 The photo-induced exo selectivity was observed in other classic Diels±Alder reactions. Data relating to some exo adducts obtained by reacting cyclopentadiene or cyclohexadiene with 2-methyl-1,4-benzoquinone, 5-hydroxynaphthoquinone, 4-cyclopentene-1,3-dione and maleic anhydride are given in Scheme 4.13. The presence and amount of Et3 N plays a decisive role in reversing the endo selectivity. The possibility that the prevalence of exo adduct is due to isomerization of endo adduct under photolytic conditions was rejected by control experiments, at least for less reactive dienophiles. Indole is a weak dienophile in normal Diels±Alder reactions and must be activated by electron-withdrawing substituents at C-2 and C-3. High Diels±Alder Reaction Facilitated by Physical and Chemical Methods 165 temperatures and long reaction times are necessary in any case. In contrast, indole gives cycloaddition with electron-rich dienes under mild conditions by a photo-induced electron transfer reaction [46]. Thus by irradiation of the indole 57, the diene 58 and the sensitizer 59 in the presence of acetyl chloride, the cycloadduct 60 was obtained in 67 % yield after 8 h (Equation 4.6). H 59, hν, 15 ⬚C + MeCOCl + DCM, NaHCO3 8 h, 67 % endo/exo = 82:18 N H 57 N H COMe 60 58 4:6 Ph BF4 Ph O Ph 59 Acetylchloride is a trapping agent that allows the reaction to go completion, transforming the product into a less oxidizable compound.The results of other reactions between indole (57) and substituted cyclohexa-1,3-dienes show that the photo-induced Diels±Alder reaction is almost completely regioselective. In the absence of 59 the cycloaddition did not occur; the presence of [22] adducts was never detected. Experimental data support the mechanism illustrated in Scheme 4.14. The intermediate 57a, originated from bond formation between the indole cation radical and 58, undergoes a back-electron transfer to form the adduct 60 trapped by acetyl chloride. 58 + [59] + [59] N N H H 57 H H MeCOCl N H COMe N H H N + [59] H 57a 60 Scheme 4.14 166 Photo-Induced Diels±Alder Reaction The investigation was recently enlarged to include functionalized exocyclic dienes 61±63 (Figure 4.2) which are promising starting materials for the synthesis of carbazole derivatives [47]. Some significant results from the photocycloadditions with 5-substituted indoles 64 catalyzed by 59 and 65 (Figure 4.2) are reported in Table 4.13. cis-Bridged adducts were always obtained with high regioselectivity; with 62 and 63 a 1:1 mixture of diastereoisomers with the stereogenic centers bearing the phenyl group were obtained. The cycloaddition of photoenol of o-methylbenzaldehyde 66 with 5-alkylidene-1,3-dioxane-4,6-dione derivatives 67 is an example of a photo-induced Diels±Alder reaction in which one component, the diene in this case, is generated by irradiation [48]. The yields of some cycloadducts 68, generated by photo-irradiation of a benzene solution of 66 and 67 at room temperature, are reported in Table 4.14. The first step of the reaction is the formation of (E)-enol 69 and (Z)-enol 70 (Equation 4.7) by an intramolecular hydrogen abstraction of 66 followed by a stereo- and regioselective cycloaddition with CO2Et O N CO2Et R CO2Me R Ph Ph 61 N N 62 a: R = Ts 63 a: R = Ac b: R = Ac b: R = COPh c: R = CO2Et Ar R N Ar Ar O H 65 64 a: R = H b: R = CO2Et Ar =p-CH3O-C6H4 c: R = CN d: R = NO2 Figure 4.2 Table 4.13 Photoinduced Diels±Alder reactions of indoles 64 and dienes 61±63 with sensitizers 59 and 65 Indole Diene 64b 64d 64b 64c 64d 64d 64d 61 61 62a 62a 62b 62c 63a Sensitizer Yield (%) 59 65 59 59 65 65 65 61 80 50 61 63 60 58 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 167 Table 4.14 Diels±Alder reactions of photoenol of 66 with 67 HO O O CHO R1 O + O R2 R3 hν (100W) R4 PhH, r.t. R2R1 O 66 67 Entry R1 1 2 3 4 5 6 i-Pr H ± CH2 5 ± Cy H i-Pr H ± CH2 5 ± ± CH2 5 ± O R3 O O R4 68 R2 R3 R4 t(h) Me Me Me Me Me Me ± CH2 4 ± ± CH2 4 ± ± CH2 5 ± Yield (%) 3 2 3 2 2 3 80 53 62 54 69 65 67. Stereochemical analysis shows that the adducts of entries 1, 3 and 6 in Table 4.14 are derived by an exo-approach of 69 with their respective dienophiles. OH CHO hν OH + 66 69 4:7 70 The coupling photolysis±Lewis acid is also sometimes effective in promoting a Diels±Alder reaction. Thus, cationic (R,S)-(ON)Ru-salen homochiral complex 71 catalyzed the Diels±Alder reaction between Danishefsky's diene and benzaldehyde when the reagents were exposed to direct sunlight through a window or to incandescent light in t-butyl methyl ether (TBME)[49] (Equation 4.8). The reaction in the dark was very slow and only 3 % ee was detected. OCH3 1. 71, hν, TBME O PhCHO + OSTM 2. CF3CO2H (S) NO N Ru O Cl O Ph Ph N Ph hν T (⬚C) t (d) Yield (%) ee (%) sunlight r.t. 7 54 79 60 W 0 2 26 83 O 4:8 (R) 71 168 Photo-Induced Diels±Alder Reaction As shown above, a high regioselectivity is a characteristic of photo-induced Diels±Alder reactions. A further example is the photochemical reaction between 2-electron-withdrawing substituted thiophenes and phenylacetylene; when the reactants were irradiated in acetonitrile, ortho-substituted biphenyls were obtained [50] (Equation 4.9). When sensitizers were used no biphenyl adduct was observed. It was suggested that the reaction occurs via triplet excited thiophene derivative which gives a radical intermediate by reacting with phenylacetylene; this intermediate can undergo ring-closure directly to phenyl with sulfur elimination or lead to 1,4-cycloaddition adduct with successive sulfur extrusion. S R R R + hν (250 W), CH3CN Ph C CH Ph Ph S 4:9 r.t., 4.5−24 h, 50−91% R = NO2, COMe, CHO The low solubility of fullerene (C60 ) in common organic solvents such as THF, MeCN and DCM interferes with its functionalization, which is a key step for its synthetic applications. Solid state photochemistry is a powerful strategy for overcoming this difficulty. Thus a 1:1 mixture of C60 and 9-methylanthracene (Equation 4.10, R Me) exposed to a high-pressure mercury lamp gives the adduct 72 (R Me) with 68 % conversion [51]. No 9-methylanthracene dimers were detected. Anthracene does not react with C60 under these conditions; this has been correlated to its ionization potential which is lower than that of the 9-methyl derivative. This suggests that the Diels±Alder reaction proceeds via photo-induced electron transfer from 9-methylanthracene to the triplet excited state of C60 . R R hν, 28 ⬚C C60 + 4:10 9h C60 R = H, Me 72 The photo-oxygenation of 1,3-dienes by singlet oxygen [52] gives peroxides which, especially those of an aromatic type, release oxygen upon cycloreversion and therefore are a form of chemically stored singlet excited oxygen molecules. The photooxygenation is carried out in the presence of sensitizers such as Rose Diels±Alder Reaction Facilitated by Physical and Chemical Methods 169 Bengal, Methylene Blue, haematoporphyrin and tetraphenylporphyrin and, generally, in organic solvents. Some examples are illustrated in Scheme 4.15. Peroxide products obtained from fatty acid precursors [61] or from cyclopentadienes [62] are of interest as pharmaceuticals or for biomedical studies; others are versatile starting materials for further transformation. O O O O [53] O [60] OO O [54] O [55] 1O 2 [59] O O + O O O ( )n O [56] [58] O ( )n O O O [57] O O O Scheme 4.15 The primary interaction of singlet oxygen, produced by energy transfer from the excited sensitizer, with the diene can give rise to an exciplet that then collapses to peroxide, to a 1,4-biradical or to a 1,4-zwitterion; alternatively, the adduct is the result of a concerted action without the involvement of an intermediate. Detailed kinetic Diels±Alder investigations of singlet oxygen and furans indicate that the reactions proceed concertedly but are asynchronous with the involvement of an exciplex as the primary reaction intermediate [63]. 170 4.5 Diels±Alder Reaction in Molecular Cavities DIELS±ALDER REACTION IN MOLECULAR CAVITIES The transition state of concerted Diels±Alder reactions has stringent regio- and stereochemical requirements and can assume settled configurations if the reaction is carried out in a molecular cavity. Cyclodextrins, porphyrin derivatives and cyclophanes are the supramolecular systems that have been most investigated. Cyclodextrins (CDs) are cyclic a-1,4-linked d -()-glucopyranose units (a-CD six units; b-CD seven units) that form inclusion complexes with a variety of hydrophobic molecules in aqueous medium [64]. The CDs serve as the reaction vessel, and the aggregation of the reagents within the cavity can enhance the reactivity and selectivity of the process. There are many examples of CD-facilitated Diels±Alder reactions [65]. The Diels±Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile are accelerated when carried out in water in the presence of b-CD but are slower with a-CD [65a] (Scheme 4.16). This is in agreement with the observation that the transition states of these cycloadditions fit into the hydrophobic cavity of b-CD but not in the smaller a-CD cavity. R R + + H2O CD H R R T(8C) COMe CN 20 30 ka a CD =k 0.6 0.8 kb CD =k a 2.5> 9.0 a Relative second-order rate constants of reactions performed in water in the presence and absence of CD. Scheme 4.16 The importance of the relationship between the macrocycle cavity and the binding of two reagents is shown by the cycloadditions of cyclopentadiene with diethyl fumarate and ethyl acrylate in aqueous solution. The presence of b-CD strongly accelerates the first cycloaddition, while it slows down the reaction rate of the second, probably because the cavity favors the binding of two molecules of either diene or dienophile [65c]. Intramolecular Diels±Alder reactions employing furan as the diene component are an effective step in the synthesis of many natural products, but difficulties are sometimes encountered due to the poor dienic character of the aromatic ring. Using CDs can help to overcome this problem. Thus, when 73 is heated in water at 89 8C for only 6 h a 20 % epimeric 1:2 mixture of 74 and 75 is Diels±Alder Reaction Facilitated by Physical and Chemical Methods 171 formed [65b] (Scheme 4.17), while in the presence of 1 eq. of b-CD, 91 % of the adducts are obtained. No significant yield enhancement was observed when aCD was employed. The analogous compounds 76 and 77 did not show any tendency to cyclize under these conditions. HO S O S 89 ⬚C 6h O O HO S S 73 + 74 Medium Yield (%) 74/75 H2 O H2O + α-CD H2O + β-CD 1:2 75 R R HO 76 R = Me 77 R = OEt 20 25 91 1:1.5 S HO S O Scheme 4.17 The intramolecular Diels±Alder reaction of 78 was investigated during the synthesis of isoquinoline alkaloids [65i]. No reaction occurred when solid-phase conditions were used (Florosil in DCM and CaCl2 ) or when a variety of Lewis acids were employed (SnCl4 , BF3 , RAlCl2 , Ti i Pr4 ±TiCl4 ). A 56 % yield of 79 was obtained by carrying out the cycloaddition in toluene in a sealed tube at 200 8C. b-CD catalysis in water under milder conditions (Equation 4.11) improved the conversion to 84 %. O O N O O H2O + b-CD 65−90 ⬚C 84% 78 N H O H O 4:11 79 The intramolecular hetero-Diels±Alder reactions of 4-O-protected acylnitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 172 Diels±Alder Reaction in Molecular Cavities Table 4.15 Diels±Alder reactions of acylnitroso compounds OR1 Pr4NIO4 NH O 0 ⬚C, 1 min OH O N O R2 81 80 R1 R2 Medium Bn Bn Bn Bn MOM MOM MOM Bn Bn Bn H H H H H H H Eta Et Et CHCl3 H2 O H2 O bCD H2 O gCD H2 O H2 O bCD H2 O gCD H2 O-DMSO H2 O-DMSOb aCD H2 O-DMSOb bCD b N OR1 H + O O O R2 a OR1 H OR1 R2 82 (endo ) N O R2 83 (exo ) endo/exo Yield (%) 1.3 4.1 2.8 1.7 4.4 3.1 3.4 4.2 4.1 2.7 76 87 93 86 93 91 74 77 80 75 Oxidation with NalO4 H2 O-DMSO 5 : 1. As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels±Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 8C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. In contrast, the trimer 89 with ethyne and butadiyne links stabilizes the thermodynamically disfavored endo transition state, and the endo adduct 86 is rapidly and almost exclusively formed. Diels±Alder Reaction Facilitated by Physical and Chemical Methods Ar + O Ar P 87 (exo) Ar Ar N Ar N H H O O Ar 86 (endo) R N Ar + N 85 R O C2D2Cl4 O O O H Ar 30 ⬚C N 84 H O O Ar 173 P Ar Ar Ar Zn N N Ar Ar P R R P Ar P P Ar Ar P Ar 89 R = CH2CH2CO2Me 88 R = Et Host Selectivity krel (endo)a none 88 89 exo + endo exo endo 500 aRelative krel (exo)a Ar = 1000 to rates in the absence of host at 30 ⬚C. Scheme 4.18 An example of a cyclophane-type cavity is the azacyclophane CP66 supramolecular system which provides a lipophilic cavity with an internal width of Ê , as well as positive charges which accelerate and increase approximately 6.5 A the selectivity of the process. The Diels±Alder reaction of cyclopentadiene with diethylfumarate at 20 8C in 10 % and 50 % dioxane±water is accelerated by the presence of CP66 by 2.9 and 1.5 times, respectively [65c] (Equation 4.12). N (CH2)6 N CO2Et + EtO2C CO2Et 4 Cl H H CO2Et 4:12 N (CH2)6 N [CP 66] 174 4.6 Micelle-Promoted Diels±Alder Reaction MICELLE-PROMOTED DIELS±ALDER REACTION Micellar medium has received great attention because it solubilizes, concentrates and orientates the reactants within the micelle core and in this way accelerates the reaction and favors the regio- and stereoselectivity of the process [68]. In addition the micellar medium is cheap, can be reused, is more versatile than cyclodextrins and more robust than enzymes. With regard to Diels±Alder reactions, we may distinguish between (i) those in which one or both reagents are surfactants which make up the micellar medium, and (ii) those that are carried out in a micellar medium prepared by a suitable surfactant. 4.6.1 Diels±Alder Reactions of Surfactant Reagents One of the first examples of Diels±Alder reactions of surfactant reagents was reported by Keana [69]. The surfactant dienes 90 and 91 (Figure 4.3), analogs to commercially available sodium dodecyl sulfate (SDS) and dodecyl maltoside, react rapidly with highly hydrophilic and reactive triazoline dione 92 in water at 25 8C forming, quantitatively, the corresponding adducts. The Diels±Alder reactions with less potent dienophile 93 gave, similarly, quantitative yields in 0.5 h and 3 h with 90 and 91, respectively. N N O N O O OR ( )7 N O C6H4p-SO3 90 R = SO3Na 91 R = β-maltose SO3Na 92 93 Figure 4.3 Jaeger and coworkers investigated the ability of aqueous surfactant aggregates to control the regiochemistry of Diels±Alder reaction of a surfactant 1,3-diene with a surfactant dienophile [70]. Surfactant 1,3-diene 94 reacts with dienophile 95, giving a mixture of endo/exo adducts 96 whose regiochemistry is the opposite of that expected if the reagents had reacted in their preferred orientation within the mixed micelle. This demonstrates the importance of orientational effects in the aggregates [70a] (Equation 4.13). Diels±Alder Reaction Facilitated by Physical and Chemical Methods NHCO2(CH2)6NMe3Br 175 NHCO2(CH2)6NMe3Br COC6H4p(CH2)5Me COC6H4p(CH2)5Me + 4:13 95 SO2C6H4p(CH2)5Me SO2C6H4p(CH2)Me 96 94 The substituents at C-2, C-3 within diene 97 and those at C-1, C-2 within dienophiles 98±100 are electronically and/or sterically equivalent with respect to diene and dienophile reaction centers, respectively, and therefore cycloaddition should not display regiochemical bias in the absence of orientational effects. The Diels±Alder reactions of 97 prepared in situ with 98±100 gave an excess of 101 (Scheme 4.19) [70b], which are the expected regioisomers if the reagents react in their preferred orientations within a mixed micelle with an ammonium head group at the aggregate±water interface and the remainder in the micelle interior. CO2(CH2)6NMe3Br Me3N-(CH2)4-p C6H4-S Me-(CH2)7-p C6H4-S + RO pH = 7.0 O 97 130 ⬚C, 2h 98 R = Me 99 R = Bu 100 R = (CH2)7Me CO2(CH2)6NMe3Br Me3N-(CH2)4-p C6H4-S Dienophile 101/102 98 99 100 1.4 2.0 2.6 Yield (%) 63 85 90 Me-(CH2)7-pC6H4-S CO2R 101 + CO2R Me3N-(CH2)4-p C6H4-S Me-(CH2)7-pC6H4-S CO2(CH2)6NMe3Br 102 Scheme 4.19 A higher regioselectivity was observed [70c] in the cycloaddition in water at 25 8C of diene surfactant 103 with 100 (Equation 4.14, 104/105 6.7:1) in agreement with the expectation that the organizational ability of aqueous aggregates is higher at lower temperatures. 176 Micelle-Promoted Diels±Alder Reaction I Me3N-(CH2)6-S + 100 95% Me(CH2)7Me2Si 103 H2O, 25t ˚C, 52 h S CO2(CH2)6NMe3X S CO2(CH2)7Me CO2(CH2)7Me S 4:14 + 104 CO2(CH2)6NMe3X S 6.7 : 1 105 Parallel studies on the cycloadditions of non-surfactant dienes 106 and 107 and the dienophile 108 (Figure 4.4), analogs of 97, 103 and 98±100, respectively, show that the regioisomer adducts were, in this case, obtained in equal amounts, supporting the idea that orientational effects in micelles promote the regioselectivity of a Diels±Alder reaction of a surfactant diene and a surfactant dienophile. HO-(CH2)4-pC6H4-S Me2N-(CH2)6-S Me-(CH2)7-pC6H4-S Me(CH2)7Me2Si 106 107 CO2(CH2)6Br RO2C 108 R = Me, Bu, (CH2)7Me Figure 4.4 4.6.2 Micellar Catalysis There are few examples of the influence of micelles on reactivity and selectivity of Diels±Alder reactions, and the observed effects are sometimes capricious. Compared to the reaction in pure water, modest [71] and exceptional [72] accelerations and even retardations [65e, g, 73] have been observed, and little [73b, 74] and high [75] endo/exo diastereoselectivities were found. The cycloadditions of cyclopentadiene 1 and its spiro-derivatives 109 and 110 with quinones 52, 111 and 112 (Scheme 4.20), carried out in water at 30 8C in the presence of 0.5 % mol. of cetyltrimethylammonium bromide (CTAB), gave the endo adduct in about 3 h with good yield [72b]. With respect to the thermal Diels± Alder reaction, the great reaction rate enhancement in micellar medium (Scheme 4.20) can be ascribed to the increased concentration of the reactants in the micellar pseudophase where they are also more ordered. The catalytic activity of micelles bearing catalytically active metal counterions (Lewis acid-surfactant combined catalysts, LASCs) on Diels±Alder reactions was recently investigated [72a, 76]. Diels±Alder Reaction Facilitated by Physical and Chemical Methods O 177 O R O 1 109 a b 110 O 111 52 R = H 112 R = Me Reagents MR(Yielsd %)a TR (Yield %)b 109+111 110+111 1+52 1+112 109+52 110+52 66 78 68 86 75 76 60 45 50 0 53 62 Micellar reaction (H2 O, CTAB, 30 8C, 3h). Thermal reaction (PhMe110 8C, 10-12h). Scheme 4.20 Engberts and coworkers [72a] studied kinetically the influence of micelles of CTAB, SDS, C12 E7 and LASCs, such as copper and zinc didodecyl sulfate [Cu DS2 , Zn DS2 ], on the Diels±Alder reactions of cyclopentadiene with 2propen-1-ones 113 in aqueous medium at 25 8C. The endo adduct was the highly prevalent diastereoisomer. The results are reported in Table 4.16. Classic micelles (SDS, CTAB, C12 E7 ) (Table 4.16, entries 2, 3 and 4) slow the reaction down, presumably because the dienophile probably resides primarily in the aqueous phase where the concentration of diene is reduced due to its partial solubilization by the micelles. The presence of Cu(II) ions accelerates the reaction (entries 6 and 7), but a comparison with the reaction catalyzed by Cu NO3 2 only (entry 5) once again shows that micelles of CTAB and C12 E7 inhibit cycloaddition. An extraordinary micellar catalysis was found when the reaction was carried out in the presence of Cu DS2 , that is, when the diene, dienophile and copper ion bind simultaneously to the micelle. Comparing this catalytic effect of the reaction of 1 with 113a (entry 8: 6243) to that found for the same uncatalyzed reaction in acetonitrile (Chapter 6, Table 6.5: 287), the Cu DS2 micelles in water accelerate the reaction of 1 with 113a by 1:8 106 times. Different results were obtained by Kobayashi and colleagues [76] performing the Diels±Alder reaction of 2,3-dimethyl butadiene with N-butylmaleimide in water in the presence of various dodecyl sulfate (DS) and dodecane sulfonate (DCS) LASCs [M DSn : M Sc, Cu; n 3, 2; M DCSn : M Sc, Yb, Mn, Co, Cu, Zn, Na, Ag; n 3, 2, 1]. Unexpectedly, no acceleration was observed with respect to the reactions carried out in water only, and no catalytic effect was found also by using a bidentate dienophile which, in principle, should be able to coordinate the metal cation in the LASC system. 178 Micelle-Promoted Diels±Alder Reaction Table 4.16 Micellar catalysis of Diels±Alder reactions of cyclopentadiene (1) with 3-(psubstituted phenyl)-1-(2-propen-1-one (113) in water at 25 8C. Relative rate constants (krel ) to the reactions performed in sole water C6H4-p-R + 1 O O C6H4-p-R H2O 25 ⬚C H 2-Py O 113 a: R = NO2 b: R = CH2SO3Na c: R = (CH2NMe3)Br d: R = H (endo ) 2-Py + C6H4-p-R 2-Py (exo ) krel kcat =kH2 O Entry Catalyst 1 2 3 4 5 6 7 8 none SDS CTAB C12 E7 a Cu NO3 2 (10 2 m ) CTAB Cu NO3 2 (10 C12 E7 Cu NO3 2 (10 Cu DS2 (5:10 3 m )b a b 2 2 m) m) 113a 113b 1 0.91 0.90 0.83 808 Ð Ð 6243 1 0.83 0.16 0.93 793 86 620 3161 113c 1 0.60 0.82 0.84 869 751 698 6245 Dodecyl heptaoxyethylene ether; Copper didodecyl sulfate The micellar effect on the endo/exo diastereoselectivity of the reaction has also been investigated. The endo/exo ratio of the reaction of cyclopentadiene with methyl acrylate is affected little (compared to water) by the use of SDS and CTAB [73b], while a large enhancement was observed in SDS solution when nbutyl acrylate was the dienophile used [74]. The ratio of endo/exo products in the reaction of 1 with 113c is not affected by CTAB, SDS and C12 E7 [72a]. Recently Diego-Castro and Hailes [75] carried out a careful investigation on the effect of cationic surfactant CTAB and anionic surfactant SDS on the reactivity and stereoselectivity of aqueous Diels±Alder reaction between cyclopentadiene and a range of acrylate esters at room temperature. The surfactants were used at their critical micellar concentration, and the pH effect of the aqueous solution was also investigated to determine the optimum conditions for obtaining the highest diastereoselectivity. Some results are reported in Table 4.17, together with those obtained in the absence of surfactant, after reaction times of 4 h and 72 h. As the reaction time increases the endo/exo decreases because of the reversibility of Diels±Alder reactions that favor the more thermodynamically stable exo adduct. The endo/exo ratio decreases as the chain length of the acrylates increases. The pH of the aqueous medium also plays an Diels±Alder Reaction Facilitated by Physical and Chemical Methods 179 Table 4.17 CTAB effect on the Diels±Alder reactions between cyclopentadiene and acrylate esters O O H2O OR + + OR r.t. O OR A (endo) B (exo) H2 O H2 O CTAB 4h R Yield Me Et Me CH2 8 a 5 65 35 a 72 h A/B Yield 9.3 6.0 1.8 89 79 80 a 4h A/B Yield 6.6 4.8 1.7 21 92 29 a 72 h A/B Yield 18 7.2 1.2 80 92 70 a A/B 6.5 5.5 1.7 Yield (%) important role. Thus when the cycloaddition of nonyl acrylate with cyclopentadiene was carried out in water alone, the highest diastereoselectivity (endo/exo 2.3) was observed at pH 3, while when the reaction was performed in the presence of CTAB at the same pH values a ratio of 1.7 was found and values higher than about 2.0 were not observed in the pH range 1 to 9.5. The Diels±Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2:1 mixture of endo/exo adducts was obtained with 75 % yield. Only 15 % of ee was observed, which compares well with the results quoted for Diels±Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels±Alder reaction. Cl N H OH 114 Figure 4.5 180 Biocatalyst-Promoted Diels±Alder Reaction 4.7 BIOCATALYST-PROMOTED DIELS±ALDER REACTION Biocatalysts have received great attention in these last few years. Due to their capacity to perform asymmetric transformations under mild conditions [78], they have been useful tools for synthesizing optically active organic molecules. They promote a variety of chemical transformations, including the syntheses of esters and amides and oxidations, reductions, eliminations and carbon± carbon forming. Little is known about biocatalyst-promoted Diels±Alder reactions. 4.7.1 Proteins and Enzymes Catalysis The aqueous [42] cycloaddition reaction of 1,4-naphthoquinones 115 with methoxy cyclohexadiene performed in the presence of bovine serum albumin (BSA) is one of the first examples of protein-promoted Diels±Alder reactions [79]. Some results are reported in Table 4.18. The globular protein does not affect the regioisomer ratio of adducts. The highest enantiomeric excess was obtained in the cycloaddition of juglone 115 (R H) with 1-methoxy-1,3cyclohexadiene 116. Rao and colleagues [80] reported the first example of baker's yeast-catalyzed Diels±Alder reaction. Reactions of cyclopentadiene (1) with dienophiles 119 and 120 (Scheme 4.21) in the presence of baker's yeast at pH 7.2 afford prevalently the exo adduct with the exception of crotonic acid 120a. Table 4.18 Diels±Alder reactions in aqueous medium in the presence and in the absence of bovine serum albumin O O O OCH3 25 ⬚C + + 18 h OR O 115 OCH3 116 OR O OCH3 OR 117 R Conditions 117/118 Yield (%) H H Me Me n-C8 H17 n-C8 H17 H2 O H2 O/BSA H2 O H2 O/BSA H2 O H2 O/BSA 2.5:1 2.5:1 1:7.5 1:6 1:4 1:3.5 99 41a 99 76 58 67 a Dehydrogenated isomeric adducts were also present. O 118 ee (%) 38 3 0 Diels±Alder Reaction Facilitated by Physical and Chemical Methods H CO2R H CO2R 119 a: R = H, 74% b: R = Et, 78% 181 CO2R CO2R (exo) H2O/EtOH pH 7.2, 37 ⬚C, 48 h R2 1 + H R1 R1 H (exo) R2 R1 R2 (endo) 120 a: R1 = Me, R2 = COOH, 72% b: R1 = Ph, R2 = COOH, 76% endo/exo Medium, Cat. H2 O H2 O + baker's yeast a 119a 119b 98:2 0:100 93:7 0:100 120a 120b 100:0a 90:10 100:0a 3:97 reaction yield very low. Scheme 4.21 The involvement of Diels±Alder reactions in the biosynthesis of naturally occurring compounds was hypothesized at least 20 years ago, but Diels± Alderase, the enzyme that catalyzes the reaction, was only isolated by Oikawa and colleagues [81] in 1995 in extracts of Alternaria solani, a fungus that causes early blight disease in potato and tomato plants. The fungus produces toxins known as solanapyrones which were biosynthesized via Diels±Alder reaction with exo selectivity, which cannot be achieved via usual chemical synthesis. Laboratory experiments show that the crude enzyme, containing solanapyrone synthase, catalyzes the Diels±Alder reaction of prosolanapyrone 122 to give the (±)-solanapyrone A 123 with excellent enantioselectivity (99 % ee) and relatively high exo-selectivity (6:1) (Scheme 4.22). Interestingly the solanapyrone synthase also catalyzes the oxidation of prosolanapyrone 121 to 122, so a single enzyme catalyzes a two-step reaction of 121 to 123. The biosynthesis of solanapyrones via Diels±Alder reaction has also been proposed [81b,c]. 182 Biocatalyst-Promoted Diels±Alder Reaction OHC OMe OHC OMe OHC OMe Diels−Alderase O O O O O H O H 122 123 (exo) −2H Diels-Alderase OMe OHC OMe OHC HOH2C O O O H O O 121 a OMe O (endo ) Substrate Medium, cat. T(8C) t(h) 122 121 H2 O H2 O, pH 7 Enzyme 110 30 3 2 H 124 124/123 96:4 15:85a Yield (%) 62 61 123 ee > 98%; 124 ee = 67% Scheme 4.22 An interesting combination of enzymatic with non-enzymatic transformation in a one-pot three-step multiple sequence was reported by Waldmann and coworkers [82]. Phenols 125 in the presence of oxygen and enzyme tyrosinase are hydroxylated to catechols 126 which are then oxidized in situ to ortho quinones 127. These intermediates subsequently undergo a Diels±Alder reaction with inverse electron demand by reaction with different dienophiles (Table 4.19) to give endo bicyclic 1,2-diketones 128 and 129 in good yields. Another example of an enzymatic one-pot multiple Diels±Alder reaction is illustrated in Table 4.20 [83]. Racemic furfuryl alcohols 130 in the presence of ethoxy vinyl methyl fumarate 131 and enzyme TOYOBO-LIP undergo enzymatic acylation followed by kinetic enzymatic resolution to give the acyl derivatives 132 which then affords the adducts 133 and 134 by intramolecular Diels±Alder reaction; 3-methyl-furfuryl alcohol 130 (R Me) in acetone gives the best results. Diels±Alder Reaction Facilitated by Physical and Chemical Methods 183 Table 4.19 Multiple hydroxylation±oxidation Diels±Alder reactions initiated by tyrosinase OH OH O OH Tyrosinase O2 O R2 O O O + O O2, CHCl3, r.t. R1 R1 125 R1 R1 127 126 R1 R2 t(d) H Me i-Pr Br F Me Me Me OEt OEt OEt OEt OEt OPr OBu OBu R2 128 128/129 3 2.5 2 0.8 0.8 1 1 1 R2 R1 129 Yield (%) 19 33 1 >99 >99 3 3 3.2 70 77 70 43 63 85 67 78 Table 4.20 Asymmetric Diels±Alder reactions via enzymatic kinetic resolution CO2Me O O R OEt O OH 131 Toyobo-lip 30 ⬚C 130 4.7.2 R R Diels-Alder O 132 MeO2C O O + O CO2Me O R H O O MeO2C 133 O H O 134 R Solvent t(d) de 133 (ee) 134 (ee) Yield (%) H H Me Me Me2 CO THF Me2 CO THF 8 8 1 1 24 24 100 100 79 81 84 84 81 48 Ð Ð 32 28 43 37 Antibody Catalysis In the last 10 years organic chemists have shown great interest in antibodies that can promote a variety of chemical reactions, even those that are not catalyzed by natural enzymes [84]. 184 Biocatalyst-Promoted Diels±Alder Reaction The use of antibodies is based on the Jencks postulate which says that antibodies generated against an organic molecule resembling the transition state of a given reaction should catalyze this process [85]. Most monoclonal antibodies are prepared for synthetic purposes by displaying a small organic molecule (hapten), resembling the transition state of the reaction under study (generally reaction products or analogs), on a carrier protein to be recognized by the immune system that produces the antibody. Catalytic antibody 1E9, the first catalytic antibody discovered for Diels± Alder reaction, catalyzes the cycloaddition between tetrachlorothiophene dioxide and N-ethylmaleimide (Equation 4.15) [86]. Cl SO2 O2S Cl H O Cl H Cl N Cl Et O O Cl + N Et Cl Cl O Cl −SO2 135 Cl Cl Cl Cl Cl H H Cl O O Cl N Et Cl Cl O 136 4:15 O N (CH2)5CO2H 137 The reaction product 136 is not an appropriate hapten for generating catalytic antibody as it does not closely resemble the reaction intermediate 135. Antibody 1E9 was prepared against hapten 137, a stable analog of 135, and the catalyst promoted the Diels±Alder reaction with multiple (> 50) turnovers. Constrained bicyclo [2.2.2] octene haptens 140 and 141 elicit antibody catalysts 22C8 and 7D4 that change the stereoselectivity of the Diels±Alder reaction between 4-carbethoxy-trans-1,3-butadiene-1-carbamate and N,N-dimethylacylamide[87a] (Scheme 4.23). In the absence of catalysts, the endo adduct 139 is favored over the exo 138 both in refluxing toluene (66:34) and in aqueous buffer at 37 8C (85:15). Hapten 140 induces the antibody 22C8 which furnishes the exo adduct 138 exclusively with high enantioselectivity, while immunization with hapten 141, that mimicked the endo approach, results in the antibody catalyst 7D4 that favors the formation of endo adduct 139. A new approach to hapten design for elicitation of Diels±Alder catalytic antibodies by using the dicyclopentadienyl system of ferrocene as haptenic group has been successively developed [87b]. New Diels±Alderases have been produced that catalyze the cycloadditions depicted in Scheme 4.23 with high enantio- and diastereoselectivity [87b]. Diels±Alder Reaction Facilitated by Physical and Chemical Methods 185 22C8 R1 (exo ) 138 R1 (endo ) 139 R + R1 7D4 R R R = NHCO2CH2C6H4COMe R1 = CONMe2 Me2N NMe2 O O NH (CH2)4COOH (CH2)4COOH NH O O 140 141 Scheme 4.23 4.8 BRéNSTED-ACID-CATALYZED DIELS±ALDER REACTION Brùnsted-acid-catalyzed Diels±Alder reactions are not frequent because of the proton sensitivity of many dienes and cycloadducts, especially when long reaction times and high temperatures are required. Examples in aqueous medium involving imines activated by protonation as dienophiles and a protonpromoted Diels±Alder reaction of glyoxylic acid with cyclopentadiene are considered in Section 6.1. The chiral catalyst 142 achieves selectivities through a double effect of intramolecular hydrogen binding interaction and attractive ± donor± acceptor interactions in the transition state by a hydroxy aromatic group [88]. The exceptional results of some Diels±Alder reactions of cyclopentadiene with substituted acroleins catalyzed by (R)-142 are reported in Table 4.21. High enantio- and exo selectivity were always obtained. The coordination of a proton to the 2-hydroxyphenyl group with an oxygen of the adjacent B±O bond in the nonhelical transition state should play an important role both in the exo±endo approach and in the si±re face differentiation of dienophile. Trifluoromethanesulfonic acid (triflic acid) in toluene greatly activates the Diels±Alder reaction of benzaldehydes with dimethylated 1,3-butadienes [89] (Table 4.22). With mono-methylated 1,3-butadienes the reaction gives less 186 Brùnsted-Acid-Catalyzed Diels±Alder Reaction Table 4.21 Asymmetric Diels±Alder reactions catalyzed by (R)-142 R1 CHO (R)-142 + −78 ⬚C, DCM, 4 h R2 O CHO O R2 R1 O B H O 142 R1 R Br Me Et Me H H H Me ee (%) Yield (%) exo/endo 99 99 92 98 99 99 99 99 99:1 99:1 97:3 99:1 satisfactory yields and the Prins product in moderate yield and low diastereoselectivity was isolated. It is hypothesized that both reactions (hetero-Diels± Alder and Prins) occur via a common carbocation intermediate which can assume differently stabilized cis and trans forms depending on the presence or absence of the methyl group at C-2 in the butadiene moiety, which favor the formation of the Diels±Alder or the Prins adduct. Table 4.22 Diels±Alder reactions catalyzed by triflic acid CHO R2 R2 R3 TfOH (aq.) + 20 ⬚C, PhMe, 14-18 h Me R1 a O Me R1 R1 R2 R3 H H H Cl NO2 OMe H H Me H H H H Me H H H H 1:1 mixture of diasteroisomers. R3 Yield (%) 72 85 82a 68 40 14 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 187 The fluoboric acid-catalyzed aza-Diels±Alder reaction of aldimine and Danishefsky's diene proceeds smoothly to afford dihydro-4-pyridones in high yields [90] (Equation 4.16). Unstable aldimines generated from aliphatic aldehydes can be prepared in situ and allowed to react under one-pot reaction conditions. This one-pot Brùnsted acid-catalyzed three-component aza-Diels± Alder reaction affords the adducts in good to high yields. OSMT R N + HBF4, −40 ⬚C R MeOH, 0.5 h 87−98% Ar Ar OMe O N 4:16 Ar = Ph, pMeO-C6H4; R = Ph, PhCH=CH, pX-C6H4 (X = NO2, Me) Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of openchain and cyclic dienes, rapidly undergo a Diels±Alder reaction [91]. Chiral a,bunsaturated ketones bearing a0 -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4 , affording Diels±Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantioselectivity of the reaction is dependent on the size of the substituent R on the a0 carbon: high levels of asymmetric induction were observed with R i-Pr (90:1) and R t-Bu (150:1) and low levels with R Me (2.7:1) and R Ph (3.0:1). Scheme 4.24 shows the postulated reaction mechanism. Gassman [92] has been a pioneer of ionic Diels±Alder reactions that proceed via in situ generation of cationic species (allylic cations) from olefinic precursors O O OEt O H O O − EtOH R R H R O O O OEt R Scheme 4.24 EtOH H O O R 188 Brùnsted-Acid-Catalyzed Diels±Alder Reaction Table 4.23 Diels±Alder reactions via vinyloxocarbenium ions O O OEt H 1. HBF4, DCM + O OH R 2. TsOH, MeOH R R T (8C) Me i-Pr t-Bu Ph 78 45 20 20 t (h) Yield (%) 2 10 16 16 58 70 60 70 by Brùnsted acids. Some of these procedures that use protic acids and aminium cation radicals as catalysts are illustrated in Scheme 4.25. A stepwise mechanism has been proposed [92d]. HBr, HSbCl4 + (pBrC6H4)3NSbCl6 95, 88% CF3SO3H H −23 ⬚C, 6min, 88% H CF3SO3H HO S HS S −23 ⬚C, 6min, 88% H S Scheme 4.25 An alternative strategy for promoting Diels±Alder reaction by proton involves the activation of dienophile by hydrogen bonding [93]. Biphenylene diol 143 (Scheme 4.26) forms doubly hydrogen-bonded complexes with a,bunsaturated carbonyl compounds, which strongly accelerate the Diels±Alder Diels±Alder Reaction Facilitated by Physical and Chemical Methods OH R2 OH n -Pr n -Pr R1 H O O R1 189 NO2 NO2 143 O H O R2 H CD2Cl2 R2 O R1 Yield (%) R1 R2 T (8C) Me H H H Me OMe H H Me Ph Me Ph r.t. r.t. 55 55 55 55 t (h) 0.16 0.5 45 73 3 144 with 143 without 143 90 76 95 74 83 13 3 10 21 13 25 13 Scheme 4.26 reactions. An ester group of acrylates blocks the formation of hydrogen bonds and consequently no acceleration is observed. Examples of hydrogen-bonding-promoted Diels±Alder reactions obtained by using alcoholic and phenolic solvents are illustrated in Section 6.2.4. Nafion-H (144), a perfluorinated resin-sulfonic acid, is an efficient Brùnstedacid catalyst which has two advantages: it requires only catalytic amounts since it forms reversible complexes, and it avoids the destruction and separation of the catalyst upon completion of the reaction [94]. Thus in the presence of Nafion-H, 1,4-benzoquinone and isoprene give the Diels±Alder adduct in 80 % yield at 25 8C, and 1,3-cyclohexadiene reacts with acrolein at 25 8C affording 88 % of cycloadduct after 40 h, while the uncatalyzed reactions give very low yields after boiling for 1 h or at 100 8C for 3.5 h respectively [95]. Other examples are given in Table 4.24. In the acid-catalyzed reactions that use highly reactive dienes such as isoprene and 2,3-dimethylbutadiene, polymerization of alkenes usually occurs; with Nafion-H, no polymerization was observed. Recently Nafion-H was successfully used in the Diels±Alder reaction of olefin acetals with isoprene and cyclopentadiene (Scheme 4.27). The reactions work well in DCM at room temperature and Nafion-H did not cleave the acetal group [96]. The recovered Nafion-H was used four or five times without affecting the yield of the cycloadducts. 190 Miscellaneous Diels±Alder Reactions Table 4.24 Nafion-H catalyzed Diels±Alder reactions in refluxing benzene Reagents MA AN BQ AN DMM AN DMF AN BQ ISa NQ 2,3-DB AC 1,3-CHa t (h) Yield (%) 5 2 15 16 25 36 40 87 92 95 94 80 93 88 (CF2-CF2)n-CF2-CF O(CF2-CF-O)m-CF2-CF2-SO3H CF3 Nafion-H (144) a At 25 8C in CCl4 . MA maleic anhydride; BQ p-benzoquinone; DMM dimethylmaleate; DMF dimethyl fumarate; NQ naphthoquinone; AC acrolein; AN anthracene; IS isoprene; 2,3-DB 2,3dimethylbutadiene; 1,3-CH 1,3-cyclohexadiene. O O R O O Nafion-H DCM r.t., 3−10 h A R R R Reaction t (h) Me Me Ph Ph A B A B 7 10 8 12 n Reaction t (h) 1 1 2 2 3 3 A B A B A B 4 4 3 4 4 4 endo/exo Yield (%) 90:10 80 81 79 84 endo/exo Yield (%) 85:15 O B O HO O ( )n O O Nafion-H DCM r.t., 3−10 h ( )n A H H ( )n B O HO 96:4 95:5 80:20 68 68 92 89 94 91 Scheme 4.27 4.9 MISCELLANEOUS DIELS±ALDER REACTIONS Base-catalyzed Diels±Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R H), the best diastereoselectivity and yields being obtained with an iPrOH=H2 O ratio of 95:5. The reaction of 146 (R Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. Diels±Alder Reaction Facilitated by Physical and Chemical Methods 191 Table 4.25 Diels±Alder reactions of 3-hydroxy-2-pyrone (145) catalyzed by cinchona alkaloids H O N + O O O O O O 0⬚C, r.t. 3−5 d R HO OH Ph O 145 146 endo R Base Solvent de (%)a H H H H H Me Me Me Et3 N CIDc CINd QUNe QUD f Et3 N CIDc CIDc i-PrOH-H2 Ob i-PrOH-H2 O i-PrOH-H2 O i-PrOH-H2 O i-PrOH-H2 O DCM EtMe2 COH t-BuOH 82 95 79 94 84 59 72 81 a b c d e f R H N Yield (%) 99 93 97 100 97 65 96 87 de (%) of endo adduct; 95:5; Cinchonidine; Cinchonine; Quinine; Quinidine Diels±Alder reaction of dienophiles, N-allylic enamides and a,b-unsaturated lactam derivatives with open chain and inner ring dienes is promoted by iodine [98]. Thus the cycloaddition of N-benzyl-N-methallyl acrylamide 147 with cyclopentadiene (1) proceeds smoothly in DMF at 78 8C in the presence of I2 (2 eq.) to give a prevalence of endo adduct (75 %) in 88 % yield (Equation 4.17). In contrast, the reaction of 147 with 1, in the absence of catalyst, affords traces of adduct after 3 days. The activation by I2 is due to the formation of cationic iodolactonization intermediate 148 (Scheme 4.28) which reacts easily with the diene, affording the dihydrooxazole 149 which is then treated with Bu4 N I to give the final adduct. With some substrates, this method of activation was proved to be more effective than the use of Lewis acids. 1. I2, DMF −78 ⬚C, 1 h, 88% Bn N + 2. n -Bu4NI O 147 1 H O N Bn endo/exo = 3:1 4:17 192 Miscellaneous Diels±Alder Reactions Bn Bn I2 N H I N 147 N Bn I O I O O I 148 149 H O n-Bu4N I N Bn Scheme 4.28 Electrochemical ionic Diels±Alder reaction has been successfully used to promote the reaction of ethylene acetals 150 with several carbo-dienes [99]. Some examples are presented in Table 4.26. These Diels±Alder reactions catalyzed by electrogenerated acid (EGA) were carried out by using platinum electrodes in DCM containing LiClO4 and Bu4 NClO4 as a source of acid catalyst. Higher endo selectivities than that obtained in the thermal reactions were observed. Reasonably, the reaction proceeds through a highly reactive allyl cation generated by the action of EGA (Equation 4.18). O O-EGA EGA O O R R Table 4.26 4:18 R O O Electrochemical ionic Diels±Alder reactions ( )n ( )n + R O −78 ⬚C, 3.5 h O 15V, ClO4 , DCM R 1 1 1 2 2 H Me Et Me Et O O 150 n R endo/exo Yield (%) 4.8 50 8.2 9.8 7.9 84 85 82 85 76 Diels±Alder Reaction Facilitated by Physical and Chemical Methods 193 The high-speed vibration milling (HSVM) technique was recently applied to the Diels±Alder reaction of fullerene C60 with condensed aromatics such as anthracene, tetracene, pentacene and naphtho[2,3-a]pyrene [100]. This is a type of mechanochemical reaction in which the mechanical energy is used as a driving force of the reaction. Thus fullerene C60 and anthracene, vigorously shaken in a stainless steel capsule with a milling ball at a rate of 3500 cycles per minute for 1 h, afford monoadduct 151 and bisadduct 152 in 55 % and 19 % yield, respectively, with 12 % unchanged C60 (Equation 4.19). The monocycloadduct was isolated in better yield than in the reaction in solution. Good yields of monoadducts were also obtained for the other condensed aromatics. The HSVM methodology is particularly advantageous for reactions which involve reactants that are hardly soluble in organic solvents. C60 HSVM + 2 + 1h, r.t. C60 C60 151 152 4:19 Among special chemical methods that facilitate the Diels±Alder reaction can be included the temporary metal connection strategy [101] that is illustrated in Table 4.27. Si, Mg and Al are used as temporary connectors of diene and dienophile moieties. The cycloaddition occurs easily due to its intramolecular nature and because the dienophilic component of reagent is now formally a vinyl carbon ion (i.e. a vinyl carbanion in 154 with M AlEt 2 ). Thus the metal-tethered 154, prepared from lithium alkoxide of 153 with the suitable metal vinyl halide, gives, by heating, the cycloadducts 156 and 157, through the Table 4.27 Diels±Alder reactions by temporary metal connection OH O 153 OH O M M R R 154 H R Mg SiMe2 AlEt 2 Mg AlEt 2 H H H Me Me + R 155 M OH 156 T (8C) t (h) 156/157 80 160 130 130 150 1 3 3 2 6 100:0 100:0 100:0 9:1 5.6:1 Yield (%) 70 70 75 60 70 R 157 194 Outlined Diels±Alder Reactions intermediates 155, that were isolated in good yield after acidification with hydrochloric acid. 4.10 OUTLINED DIELS±ALDER REACTIONS A polymer-supported silyl triflate and subsequent functionalization: synthesis and solid-phase Diels±Alder reactions of silyloxydienes [25] O N Ph Si O Si O O DCM, 25 ⬚C 14 h O O O N Ph N Ph 10% TFA 99% O O MeO OMe MeO MeO OMe OMe 13 examples Solid-phase Diels±Alder reactions of amino acid derived trienes [23] O H O Bn BnH COOH Bn COO NH2 AcOH, NaBH(AcO)3 48 h H TFA COO DCM N H N H O O 7 examples Zeolite and Lewis-acid catalysis in Diels±Alder reactions of isoprene [20b] O + H O Zeolite-Beta r.t., 32 h, 63% H various zeolites The cycloaddition reactions of unsaturated esters with cyclopentadiene on g-alumina [18] O + OMe Al2O3 50 ⬚C, 5 h + CO2Me CO2Me endo/exo ratio and yield depend on alumina activity Diels±Alder Reaction Facilitated by Physical and Chemical Methods 195 Acceleration of the Diels±Alder reaction by clays suspended in organic solvents [7] CHO + CHO K10-Fe3+ DCM, −24 ⬚C, 60 % Cycloadditions with clays and alumina without solvent [8] O O K-10 + 0 ⬚C, 5 h, 70% O O 23 examples Ultrasound-promoted cycloadditions in the synthesis of Salvia miltiorrhiza [30b] O O O US, DCM, −78 - 0 + ⬚C O H 1−3 h, 91% O H O 9 examples Asymmetric synthesis of Salvia miltiorrhiza abietanoid o-quinones: methyl tanshinonate, tanshinone IIB, tanshindiol B and 3-hydroxytanshinone [30c] O O O O US, 1. 45 ⬚C, 1 h + O CO2Me O 2. DDQ, 65% CO2Me (−)-(S) (−)-(S) On sonochemical effect on the Diels±Alder reaction [33] O US, 10 ⬚C, 1 h + CH2Br2, 18% + COMe COMe 95.1% 4.9% The Diels±Alder reaction of 2H-pyran-2-ones: part IV ± Microwave catalyzed Diels± Alder reaction of 4,6-disubstituted-2H-pyran-2-ones with 1,4-naphthoquinone and Nphenylmaleimide [41a] O O O R1 O R2 X = O, NPh + X MW, HPL 80% 4min, 51−59% O R1 X O O R2 X O R1 = pMeO-C6H4 R2 = pMeO-C6H4, Me 196 Outlined Diels±Alder Reactions Microwave-assisted Diels±Alder reactions supported on graphite [39a] Ph N N Ph Graphite, MW, IP = 30W N 1⫻10 min, 70 % HN N + N Ph Ph 5 examples Microwave-activated Diels±Alder cycloaddition reactions of 1,2-difluoro-1-chlorovinylphenylsulfone [102] + F SO2Ph + neat, 95% F SO2Ph Cl F dienes: furan, 1,3-diphenylisobenzofuran Cl MW (600W), 3 min F F F Cl SO2Ph Application of commercial microwave ovens to organic synthesis [103] O O O + O MW, 160−187 ⬚C O p -xylene, 3 min, 92% O O O MW, 400−425 ⬚C + H neat, 15 min, 25% H Diels±Alder reactions of photoenol of 2-methylbenzaldehyde with 5-alkylidene-1,3dioxane-4,6-dione derivatives [48] O CHO O hν (100 W) O PhH, 2 h, 69% + Me OHO O O O O 11 examples Stereoselective synthesis of decalines via tandem photooxidation-intramolecular Diels±Alder reactions of bis-furan [104] OMe O DCM, florisil O O OMe r.t., 48 h, 44% 1. hν (Rose Bengal) 0 ⬚C, CHCl3 O O SiMe3 2. ZnI2, 20 ⬚C 20 h, 58% O H O H O O H O OH Diels±Alder Reaction Facilitated by Physical and Chemical Methods 197 1,4-Photoaddition of -morpholinoacrylonitrile to 1-acylnaphthalenes [105] COR X CN hν (λ >280 nm) CN COR X + PhH, C6H12-Me2CO 2−48 h, 18−29% X = Morpholino, S-t-Bu R = H, Me, Ph Intramolecular Diels±Alder reactions of the furan diene (IMDAF); rapid construction of highly functionalized isoquinoline skeletons [65i] CO2Me H β-CD, H2O NHCO2Et O NHCO2Et CO2Me O 85 ⬚C, 7 d, 32% 3 examples The kinetic effects of water and of cyclodextrins on Diels±Alder reactions. Host±guest chemistry, part 18 [65c] R1 + R1 β-CD, H2O + 60 ⬚C R R R1 R R = CN, CO2Et, CO2Bu, CO2Pr, COMe, CO2H, CO2C6H11 R1 = H, CO2Et, CO2H, Various solvents Detergents containing a 1,3-diene group in the hydrophobic segment. Facile chemical modification by a Diels±Alder reaction with hydrophilic dienophiles in aqueous solution [69] OH CH2OH OOH OH O OH CH2OH OO OH N N ( )5 O + N O H2O, 25 ⬚C 20 min ( )5 N N O N O OH SO3Na SO3Na 198 Outlined Diels±Alder Reactions Regioselectivity of Diels±Alder reactions of surfactant 1,3-diene with surfactant dienophiles [70b] O OR2 R-S C8H17O S-R1 RS ∆ R-S 130 ⬚C, 2 h, 90% O C8H17O2C R = pC8H17-C6H4 S-R1 O −SO2 S O SR1 R1 = (CH2)4NMe3Br CO2R2 R2 = (CH2)6NMe3Br Micellar catalysis p4s p2s cycloaddition in aqueous media [72b] O H HO H2O, CTAB + 30 ⬚C, 3 h, 68% O O (4 2) Cycloadditions in micelles: a comparison of the product spectrum and reaction rate with reactions in solution [74] + + R R R R = CN, CO2Me, CO2Bu various surfactants; various solvents An enzyme-initiated hydroxylation±oxidation carbo-Diels±Alder domino reaction [82] O OH tyrosinase + O Me r.t., CHCl3, 1 h pH 7.0, 24% various examples O Me O + O Me 2 : 1 O O Diels±Alder Reaction Facilitated by Physical and Chemical Methods 199 Total synthesis of ( )-solanapyrone A via enzymatic Diels±Alder reaction of prosolanapyrone [81b] OHC OMe OMe O Diels-Alderase HO O O H O 30 ⬚C, pH = 7, EtOH 2 h, 51%, ee 98% H Me Studies in Lewis acid and LiClO4 (or nafion-H) catalyzed ionic Diels±Alder reactions of chiral and achiral olefinic acetals respectively [96] Nafion-H, DCM + O r.t., 4 h, 95% O H O O 6 examples endo/exo = 95:5 Diastereoselective Diels±Alder reactions via cyclic vinyloxocarbenium ions [91] O O + OEt R 1. HBF4, −45 ⬚C 10 h, DCM 2. TsOH, MeOH 74% OH O R 6 examples de = 75:1 Diels±Alder reactions: rate acceleration promoted by a bisphenylendiol [93c] O + OH OH NO2 NO2 A, CD2Cl2 H 55 ⬚C, CHO; 48 h, 60 % 11 examples A 200 References Solid-state [4 2] cycloaddition of fullerene C60 with condensed aromatics using a high-speed vibration milling technique [100] n HSVM r.t., 1 h + C60 C60 + n = 1 19% n = 2 15% C60 C60 11% An endo-selective ionic Diels±Alder reaction of a,b-enone and a,b-enal acetals catalyzed by electrogenerated acid [99] DCM, −78 ⬚C + O O ClO4 , 15 V 3.5 h, 70% O O endo/exo = 4.7 Diels±Alder reaction of N-allylic enamides and lactam derivatives through iodinemediated activation [98] H 1. I2, DMF, 25 ⬚C, 9 h N N 2. n-BuN I , 85% H O O 9 examples REFERENCES 1. Pindur U., Lutz G. and Otto C. Chem. Rev. 1993, 93, 741. 2. (a) Zaragoza DoÈrwald F. Organic Synthesis on Solid Phase, Wiley, New York, 2000; (b) Yedidia V. and Leznoff C. C. Can. J. Chem. 1980, 58, 1144. 3. Reichle W. T. 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The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 5 High Pressure Diels±Alder Reaction 5.1 INTRODUCTION Although the Diels±Alder reaction provides a rapid and convergent entry to complex polycyclic molecules, its application may sometimes be unsuccessful due to the low reactivity of reagents, diene and dienophile, and/or instability of both reagents and cycloadducts under thermal or Lewis-acid-catalyzed conditions [1]. In these cases considerable improvements have been made by applying high pressure [2]. The use of this technique is now common in the laboratory as well as in industry, since even modest pressures may have marked effects on reactions in solution. A significant example is the cycloaddition reactions of 3-methyl-2-cyclopenten-1-one (1) and 3-methyl-2cyclohexen-1-one (2) with open chain dienes [3] 3 (Equation 5.1). These bsubstituted cycloalkenones are known to be unreactive dienophiles due to the steric and electronic effects of the methyl group at the ethylenic b-carbon [4]. Thermal and catalyzed cycloadditions do not occur at atmospheric pressure, thus precluding the ready preparation of cis- and trans angularly methylated hydrindanones 4 and 6 and octalones 5 and 7, in which the angular methyl group is in a 1,3-positional relationship with the keto function. The application of high pressure (12±15 kbar) in combination with a Lewis-acid catalyst, EtAlCl2 , accelerated the reactions, offering a straightforward route [3] to these methylated bicyclic compounds which are useful intermediates in the synthesis of natural products. R3 (CH2)n 12−15 kbar + O 1 2 R2 R1 EtAlCl2, 35-65% n = 1, 2 3 R1, R2, R3= H, Me R3 (CH2)n O H 4 5 R3 (CH2)n R2 R1 O H R2 R1 5:1 6 7 The term `high pressure' means in the range 1±20 kbar (0.1±2 GPa). These pressures can be obtained with a relatively simple piston-cylinder apparatus. The Diels±Alder reaction exhibits a large negative activation volume, DVz which is the only transition state property that can readily be determined in absolute terms [5]. Diels±Alder cycloaddition also exhibits a large negative molar reaction volume, DV. Intermolecular cycloadditions have larger negative volumes (about 25 to 45 cm3 mol 1 ) than the intramolecular ones. 206 Introduction High pressure can influence reactions characterized by negative molar and activation volumes in the following aspects: (i) acceleration of the reaction, (ii) modification of regioselectivity and diastereoselectivity, and (iii) changes in chemical equilibria. The pressure dependence on the rate constant of the reaction is expressed as follows: d ln k dP DV z RT If DVz is negative, the rate constant will increase with increasing pressure. Similarly, the effect of pressure on the reaction equilibria is given by the following equation: d ln K dP DV RT If DV is negative, the application of pressure shifts the equilibrium toward the products. An interesting example of accelerating a reaction when high pressure is applied is the synthesis of a series of highly functionalized 4a,5,8,8a-tetrahydro-1,4-naphthalenediones 10 by cycloaddition of p-benzoquinone (8) with a variety of electron-poor dienic esters 9 at room temperature (Equation 5.2) reported by Dauben and Baker [6]. Using conventional methods, these heatsensitive cycloadducts are difficult to synthesize free of the isomeric hydroquinones. When the reactions were carried out under thermal conditions, the primary cycloadducts were mostly converted into the corresponding hydroquinones. CO2R O R1 + R2 O R3 8 9 O H CO2R R1 15 kbar, r.t. DCM, 60−92% O H R2 R3 5:2 10 R, R1, R2, R3 = H, Me, Et, CH2OSMDBT The cycloaddition of the poor reactive dienophile b-angelica lactone (11) with open chain dienes 12 is another interesting example of activation by high pressure [7]. Since high temperatures and/or the catalysis of strong Lewis acids are precluded due to the diene sensitivity, the cycloaddition reactions cannot be carried out at atmospheric pressure. The resulting cycloadducts 13 are of interest because they are versatile synthetic building blocks. High pressure allowed the reactions to occur under milder conditions in high yields (85±90 %) (Equation 5.3). High Pressure Diels±Alder Reaction R1 O 207 H 10−12 kbar, 40−50 ⬚C + 48−65 h, 85−90 % O O R2 11 12 R1 O H 5:3 R2 13 a R1 = H, R2 = OSMT b R1 = OSMT, R2 = OMe Pressure also provides a valuable tool in the control of the regio-and diastereoselectivity of the Diels±Alder cycloaddition. This effect is influenced by the difference between the activation volumes of parallel reactions leading to regioand diastereoisomers. A higher endo-diastereoselectivity can generally be expected because the endo transition state has a larger negative activation volume than the exo transition state. An example of regio- and stereocontrol by high pressure is the cycloaddition of the cyclohexenone-like dienophile 14 with diene 15 [7, 8] that affords the tetracyclic compound 16 which is used for the synthesis of aklavinone 17 (Scheme 5.1), the aglicone component of several members of 11-deoxyanthracyclines. Until the 1980s this technique was used mostly in mechanistic investigations to obtain information about the structure and properties of the transition state of the Diels±Alder reaction. Now, the technique is mainly used in applications of synthetic organic chemistry. O O CO2Me H O 14 H O H CO2Me 17 kbar, DCM 65 ⬚C, 48 h, 75% + O H O OMe O H O H OMe 16 15 CO2Me O OH OH O OH 17 Scheme 5.1 The solvent may be an important parameter for reactions carried out in solution, since the value of activation volume is often dependent on the solvent. A limitation may be due to the effect of pressure on the freezing temperature of 208 Open-Chain Dienes the solvent. To prevent the solvent from freezing under high pressure, temperature elevation is mostly used. 5.2 5.2.1 OPEN-CHAIN DIENES Cycloadditions with Carbodienophiles Cycloaddition reactions of (E)-1-acetoxybutadiene (18a) and (E)-1-methoxybutadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only orthoendo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the b-carbon of the olefinic double bond. The study was extended to the inverse electron-demand Diels±Alder reaction between the (E)-1-carboalkoxybutadienes 21 with ethylvinylether 22 (Figure 5.1). No reaction was observed in any case; either the starting materials were recovered or polymeric material was produced. Table 5.1 High pressure Diels±Alder reactions of (E)-1-acetoxy- (18a) and (E)-1-methoxybutadiene (18b) with acrylic and crotonic dienophiles X X Y Y 15 kbar, r.t. + 4-12 h R 19 R 18 a, X = OAc b, X = OMe 20 X Y R OAc OAc OAc OAc OAc OAc OAc OAc OMe OMe OMe CHO CHO COMe COMe CO2 Me CO2 Me CN CN CHO CHO CO2 Me H Me H Me H Me H Me H Me Me Yield (%) 81 5 45 0 19 0 5 0 47 30 0 High Pressure Diels±Alder Reaction 209 OEt R1 CO2CH2R 21 22 R, R1= H, Me, CO2Me Figure 5.1 The Diels±Alder reaction of the bicyclospirolactone 23 with E-piperylene (24) is the key step in a stereocontrolled synthetic approach to tricyclic compounds 25±27 related to Bakkenolides [10]. The cycloaddition failed at ambient pressure, but proceeded in generally good yield at high pressure and in the presence of various Lewis acids, giving mixtures of the anti-endo 25 (with respect to the CH2 SePh group), syn-endo 26 and anti-endo 27 cycloadducts (Scheme 5.2). The cycloadditions were totally regioselective and the facial diastereoselectivity seems to be dependent upon the nature of the catalyst. The preponderance of endo products was attributed to high pressure. Adducts (%) O O O TiCl2-TADDOL AlCl3 TiCl4 61 46 31 6 28 35 33 26 34 H SePh 25 O O O O O 16 kbar 82-87% + SePh 23 O H SePh 26 24 O O O H SePh 27 Scheme 5.2 a,b-Unsaturated cycloalkenones are very poorly reactive dienophiles [11] that require high temperatures to afford cycloadducts in good yields. These conditions, as well as the use of strong Lewis acids as catalysts, are precluded if sensitive hetero-substituted 1,3-butadienes are used. Cycloalkenone cycloadditions 210 Open-Chain Dienes may, however, be accelerated by pressure, thus occurring under milder conditions which often improve also selectivity. 2-Cyclopenten-1-one (28) reacts regioselectively and stereoselectively [7, 12] with the electron-rich and push±pull hetero-substituted butadienes 15 and 29 in good to high yield (Figure 5.2). The replacement of oxygen by sulfur resulted in a markedly decreased diene reactivity as shown by the complete failure of 30 and 31 (Figure 5.2) to react. CO2Me O OSMT SPh MeO2C SMe OMe 15 28 29 30 31 Figure 5.2 High pressure Diels±Alder reaction of 1-methoxy-3-(trimethylsilyloxy)-butadiene (Danishefsky's diene) (12b) with 2,3-dimethyl-5-oxocyclopent-1-ene-1carboxylate (32) is the key step in the synthesis of the 4-epi-pinguisone (33), a member of a class of sesquiterpenes, all of which have a six±five bicyclic structure with the three adjacent methyl groups in a cis configuration (Scheme 5.3) [13]. Whereas thermal cycloaddition occurred in low yield with no improvement observed by Lewis-acid catalysis, the yield was greatly improved using high pressure (13 kbar). In this case, cycloaddition, followed by hydrolysis of the intermediate silyl enol ether, gave a 4:1 mixture of enones 34 and 35 in good O + 2. CSA OSMT 32 12b E O E O 1. DCM, 13 kbar, 35 ⬚C, 7 d, 85% OMe E + O O MeO E O + O E= CO2Me 34 35 O O 33 Scheme 5.3 36 High Pressure Diels±Alder Reaction 211 yield (55 %) together with a 30 % yield of 36. The enone 34 was then converted into 4-epi-pinguisone (33). Diels±Alder reaction of 2-cyclohexen-1-one (37) with diene 38 mainly afforded the exo adduct 39, the key intermediate in the synthesis of the `bottom half' of chlorothricolide [14] (Equation 5.4). O O OAc H OAc 6 kbar; 80 ⬚C + 5:4 3 d; 78% H OSBT 37 OSBT 39 38 Similarly, cycloaddition of the cyclohexenone-like dienophile 40 with 2-trimethylsilyloxy-1,3-butadiene (41) allowed [7]: the regio- and stereoselective synthesis of tetracyclic compound 42, in high yield (Equation 5.5). O O H OSMT + S O OSMT 5:5 60 h; 75% O Ph O 40 H H 15 kbar; 50 ⬚C S 41 O Ph H 42 N-Benzoyl-1-amino-p-benzoquinone-4-dimethylketal 43 is an interesting starting substrate for the Diels±Alder-based synthesis of alkaloids [15]. The lability under typical Diels±Alder conditions, namely high temperatures and/or Lewis acids, precluded its use as dienophile. Compound 43, however, reacted with a variety of butadienes 44 under high pressure conditions at room temperature, leading to high yields of cycloadducts 45 that were converted into either annulated benzanilides or naphthanilides by being treated with p-toluenesulfonic acid [16] (Equation 5.6). The sequence of cycloaddition followed by aromatization allows the acylated quinone imine ketal to function as a synthetic equivalent of an aminobenzyne. O O N R1 Ph R2 + DCM, 25 ⬚C Ph N H R1 R2 13 kbar, 36-41% R3 MeO OMe 43 44 R1, R2, R3= H, Me, OMe, OSMT, OSMDBT H MeO OMe 45 R3 5:6 212 Open-Chain Dienes Quinone-mono-ketals 46 and 47 are also low reactive dienophiles and are sensitive to Lewis-acid catalysts. The use of high pressure overcomes this limitation [17]. As shown in Equation 5.7, cycloadditions with a variety of substituted 1,3-butadienes 48 occur regioselectively and endo-diastereoselectively in reasonable to good yields. This approach provides access to a variety of annulated benzenes and naphthalenes after aromatization of adducts 49. O R2 R4 + R1 MeO O R3 R2 13 kbar, r.t., DCM 31-96% 48 46 R1= Et, R2= H R3 R4 R1 H MeO OMe R5 OMe H R5 5:7 49 47 R1= Me, R2= H R3, R4, R5= H, Me, Ph, OSBT An example of stereocontrol by high pressure is given by the regio- and diastereoselective synthesis of hydrophenanthrenones [18] which are useful intermediates for synthesizing diterpenes and steroids, by EtAlCl2 -catalyzed cycloadditions of heteroannular bicyclic dienone 50 with (E)-piperylene (24) and 2,3-dimethyl-1,3-butadiene (51) (Scheme 5.4). The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the formation of the unusual trans adducts 53, have been explained by the facts that (i) Diels±Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. Diene O R1 R R O R 9/1 1/9 70 55 51 19/1 1/3 80 30 OH O H R1 24 R=H, R1=Me 50 51 R=Me, R1=H 24 H 52 + R R H O R1 H R1 R R H R 7 kbar 1 bar 7 kbar 1 bar H H R1 Yield (%) 52/53 H H H R 54 H R H 53 Scheme 5.4 High Pressure Diels±Alder Reaction 213 A study [19] of the cycloaddition between substituted (E)-1-phenyl-1,3-butadienes 55 and substituted 1,1-dicyanoethylenes 56 leading to cis- and transcyclohexenes 57 and 58 (Equation 5.8) has shown that diastereoselectivity is markedly dependent on pressure. Ph NC Ph CN DCM, 50 + CN R1 10 kbar, 31-96% R1 R 55 Ph CN ⬚C R 56 CN + CN R1 5:8 R 57 58 R1= Me, Et, i-Pr, t-Bu R= Me, Et, i-Pr Whereas tropones usually act as dienes in cycloaddition reactions (Section 5.4), tricarbonyl (tropone) iron 59 displays a reactivity that is almost identical to that of a normal enone. High pressure cycloadditions of 59 with 1-oxygen substituted dienes 60 gave the desired cycloadducts 61 in good to excellent yields (Equation 5.9). The subsequent decomplexation of the cycloadducts has been accomplished by treatment with CAN [20]. O R O 8-12 kbar; DCM r.t. ; 47-96% + (CO)3Fe R1 59 H R (CO)3Fe 60 H R1 5:9 61 R, R1= OAc, OSMT, OCOC6H3-3,5(NO2)2 5.2.2 Cycloadditions with Heterodienophiles Hetero-Diels±Alder reaction is a powerful methodology in the synthesis of heterocyclic compounds. Using the high pressure technique has greatly extended the synthetic applications of this methodology. Hetero-Diels±Alder reaction of perfluorooctanonitrile (62) and 2,3-dimethyl1,3-butadiene (51) allows [21] 3,4-dimethyl-6-perfluoroheptyl-2,5dihydropyridine (63) to be synthesized (Equation 5.10). Usually, perfluorocarbonsubstituted nitriles require high temperatures to undergo Diels±Alder cycloaddition [22] but, under these conditions, the dihydropyridines gradually eliminate hydrogen and are converted into the corresponding pyridines. Therefore the cycloadducts can be obtained under mild conditions. High pressure (1.5 kbar) cycloadditions between 62 and 51 at 50 8C afforded a mixture of mostly dihydropyridine 63 with the corresponding pyridine 64 (Equation 5.10). The best result (63/64 3.7:1) was obtained with a reaction time of 29 h. 214 Open-Chain Dienes C7F15 C7F15 + 1.5 kbar, 50 ⬚C + 29 h, 37% N 62 C7F15 N 51 5:10 N 63 64 Pyran derivatives, useful intermediates in the total synthesis of many monosaccharides and other natural products, have been synthesized by hetero-Diels± Alder reaction by using carbonyl compounds as dienophiles [9, 23]. A convenient synthetic route to obtain these compounds is the thermal Diels± Alder cycloaddition of 1-methoxybutadiene (18b) with carbonyl compounds, but this route is limited to aldehydes activated by an electron-withdrawing substituent. Non-activated carbonyl compounds require drastic conditions or fail to react. Application of high pressure overcomes this limitation. Cycloaddition reactions of the simple alkyl and aryl aldehydes 65 with (E)-1-methoxy-1,3-butadiene (18b) under high pressure conditions afforded adducts 66 and 67 in reasonable to good yields [2g, 23]. A marked preference for the endo-diastereoselectivity has been observed; as usual, applying pressure enforces endo-addition (Scheme 5.5). Using mild Lewis-acid catalysts [24], such as Eu(fod)3, Yb(fod)3, or Eu(hfc)3, in combination with pressure, allows good results to be obtained with the added advantage of reducing the pressure to 10 kbar [25] (Scheme 5.5). R R H + 18b OMe 18b O 65 P (Kbar) Me n-C5 H11 Ph 2-Fu + C 50-65 ⬚C + O O OMe R R 20 14 19 19.5 R1 R2 C O OMe OMe 66 67 66/67 Yield (%) P (atm) 66/67 Yield (%) 2.3 3.5 3 2.7 65 28 80 73 1 1 1 1 0.45 0 1 2 0 40 R1 Eu(fod)3, 10 kbar, DCM 50 ⬚C, 20 h, 12−81 % O R2 OMe 68 endo /exo = 6/4, 3/7 R1 = H, Me R2 = Me, Ph, 2-Fu, CO2Me, CH(Me)OSMDBT Scheme 5.5 High Pressure Diels±Alder Reaction 215 More functionalized 5,6-dihydro-2H-pyran-derivatives 71 and 72 have been prepared [26] by cycloaddition of 1-methoxy-3-trialkylsilyloxy-1,3-butadienes 69 with t-butylglyoxylate (70) (Scheme 5.6). Whereas thermal reactions did not occur in good yields because of the decomposition of the cycloadducts, application of pressure (10 kbar) allowed milder conditions to be used, which markedly improved the reaction yields. The use of high pressure also gives preferentially endoadduct allowing a stereocontrolled synthesis of a variety of substituted 5,6dihydro-2H-pyran-derivatives, which are difficult to prepare by other procedures. RMe2SiO RMe2SiO CO2n-Bu H C + O OMe 69 CO2n-Bu RMe2SiO CO2n-Bu + O O OMe OMe 72 71 70 10 kbar, r.t., 24 h R 1 bar, 80 8C, 2d Yield (%) 71/ 72 Yield (%) 71/ 72 80 85 5 10 40 30 1 4 Me t-Bu Scheme 5.6 Pressured cycloaddition of (E)-1-methoxybutadiene (18b) with 1:2,3:4-di-Oisopropylidene-a-d -galactopyranos-6-ulose (73) diastereoisomerically afforded pure cycloadduct 74, that exhibits the cis arrangement of the methoxy group with respect to the sugar moiety [27] (Scheme 5.7). Similar results were obtained with the sugar aldehydes 75 and 76. H H O C O O H OMe O O 20 kbar; DCM, 53 ⬚C + O 20 h; 70% O O O O 73 18b O 74 H C OMe O H H O O H H O H C O OBn H H O H 75 76 Scheme 5.7 H O OMe O O 216 Open-Chain Dienes Table 5.2 MeO2C High pressure Diels±Alder reactions of diene 77 with dienophiles 78 O R1 R MeO2C O H 77 MeO2C R R2 + OMe R1 R2 78 O R R2 + OMe OMe 79 80 R R1 R2 Reaction conditions 79/80 H OEt H PhMe, 110 8C TiCl4 , DCM, 78 8C 13 kbar, neat, 24 8C 1.8 0.3 5.7 H OBn Me PhH, 80 8C EtAlCl2 , DCM, 78 8C 9.5 kbar, DCM, 24 8C 3 6 19 11 46 50 OMe OMe H DCM, 40 8C 13 kbar, DCM, 25 8C Ð Ð 63 41 OMe OMe OMe 9.5 kbar, DCM, 24 8C 0.5 R1 Yield (%) 48 61 82 41 An alternative approach to the synthesis of pyran derivatives based on high pressure accelerated intermolecular inverse electron-demand Diels±Alder reaction of 1-oxo-1,3-butadienes has been developed by Boger and Robarge [28, 29]. Central to the development of this approach was the selection of appropriately matched diene±dienophile partners of the inverse electrondemand cycloaddition which permits the preparation of carbohydrates bearing a full range of selectively protected oxygen substituents. Methyl-trans-4methoxy-2-oxo-3-butenoate (77) and methyl-trans-4-phenyl-2-oxo-3-butenoate (81) underwent cycloaddition reactions with a variety of electron-rich dienophiles. Some of the results are summarized in Tables 5.2 and 5.3. All the reactions were totally regioselective and, although thermal and catalyzed cycloadditions preferentially proceed through an endo transition state, the pressure-promoted cycloadditions are more endo-diastereoselective and give higher reaction yields. High Pressure Diels±Alder Reaction Table 5.3 MeO2C 217 High pressure Diels±Alder reactions of diene 81 with dienophiles 78 O R MeO2C R1 O + 81 5.3 R2 H OPh 78 R1 R R2 MeO2C O + OPh OPh 82 83 R R1 R2 Reaction conditions 82/83 H OEt H PhMe, 80 8C EtAlCl2 , DCM, 78 8C 6.2 kbar, neat, 24 8C H OMe OBn OMe Me H 6.2 kbar, DCM, 24 8C DCM, 40 8C 6.2 kbar, DCM, 24 8C 25 Ð Ð 78 Ð 65 OMe OMe OMe 10 kbar, DCM, 24 8C 1 72 4 0.4 9 R1 R R2 Yield (%) 73 94 86 OUTER-RING DIENES Pressure-promoted stereoregular Diels±Alder reactions have been used in the synthesis of macropolycycles by Stoddart and coworkers [30]. A key feature inthis synthetic approach has been the development of a repetitive Diels±Alder reaction sequence in which three distinct levels of diastereoselectivity are achieved during each cycloaddition involving bisdiene and bisdienophile building blocks. The development of this highly efficient synthesis provided an easy entry into a new series of exotic hydrocarbons. The synthesis of the [12]-cyclacene derivative 88 is a representative example (Scheme 5.8). The chosen building blocks 84 and 85 have diastereotopic p-faces and therefore, in principle, there are eight different ways of interaction. However, the p-facial diastereoselectivities exhibited in cycloadditions with 84 and 85 are such that Diels±Alder reaction occurs preferentially at the exo-face of bisdienophile 84 and the endo-face of the bisdiene 85. Thermal equimolecular cycloaddition between 84 and 85 diastereoselectively afforded a mixture of 86 (24 %) and 87 (61 %); the 2:1 adduct 87 is formed from 86. High pressure-promoted cycloaddition (10 kbar) of 87 with bisdienophile 218 Outer-Ring Dienes 84 led to the desired [12]-cyclacene 88. The cycloaddition presumably affords the intermediate 89 which immediately undergoes a rapid intramolecular ring closure. In a different approach to 88, cycloadduct 86 reacted with bisdienophile 84 at high pressure (10 kbar) to afford nonacene 90 (Scheme 5.8). Thermal intermolecular Diels±Alder reaction of 90 with bisdiene 85, followed by the intramolecular ring closure of the cycloadduct, led to compound 88. O O + PhMe O ∆ 85 84 H O O 84 H 85 H PhMe, ∆ O DCM 10 kbar O O H H H O O 86 87 DCM 84 10 kbar O O H H H H O O 90 85 H H O O H O H H H H O PhMe ∆, 12 h H O O O DCM 10 kbar H O O H H O O 88 H H O O H 89 Scheme 5.8 The o-quinodimethanes are very reactive, unstable dienes, which are usually prepared in situ. The cycloaddition under high pressure of the dibromoo-quinodimethane 91, generated in situ from a,a,a0 ,a0 -tetrabromo-o-xylene, High Pressure Diels±Alder Reaction 219 with 2-cyclohexenone (37) directly afforded [31a] 1-(2H)-anthracenone (92), which is a useful starting material for the synthesis of polycyclic aromatic hydrocarbons (Equation 5.11). No reaction occurred under thermal conditions because of the low reactivity of 2-cyclohexenone (37). This onepot synthesis of 92 is easier than the previously reported four-step synthesis [31b]. O O CHBr + NaI, 9 kbar, DMF 5:11 60 ⬚C, 17 h, 32% CHBr 37 5.4 91 92 INNER-OUTER-RING DIENES Arylethenes are `inner-outer-ring dienes' in which the vinyl group is linked to an aromatic system. These dienes are poorly or moderately reactive; the presence of electron-donating substituents in the diene moiety markedly increases their reactivity. Their cycloadditions are usually accelerated in order to be carried out under mild conditions. 1-Vinylnaphthalene is more reactive than 2-vinylnaphthalene and styrenes. Enantiomers (M)- and (P)-helicenebisquinones [32] 93 have been synthesized by high pressure Diels±Alder reaction of homochiral ()-(2-p-tolylsulfonyl)-1,4-benzoquinone (94) in excess with dienes 95 and 96 prepared from the common precursor 97 (Scheme 5.9). The approach is based on the tandem [4 2] cycloaddition/pyrolitic sulfoxide elimination as a general one-pot strategy to enantiomerically enriched polycyclic dihydroquinones. Whereas the formation of (M)-helicene is explained by the endo approach of the arylethene toward the less encumbered face of the quinone, the formation of its enantiomeric (P)-form can be the result of an unfavourable interaction between the OMe group of approaching arylethene and the sulfinyl oxygen of 94. 220 Inner-Outer-Ring Dienes O CH2=CHSnBu3 Pd(PPh3)4, PhMe 110 ⬚C, 4 h, 65% (+) 94 O O 4 kbar, 4 d, 12% 95 O 93 (M) 97 Br OMe O PhMe ∆, 2 h, 84% 1. Me2SO4/K2CO3 Et2O, Na2S2O4 (+) − 94 O Br 2. CH2=CHSnBu3 Pd(PPh3)4, PhMe 110 ⬚C, 4 h, 63% OMe 96 12 kbar DCM 48 h 12% O O S Tol O (+) 94 CAN MeCN r.t., 2 h 59% O O O S-(+) 94 93 (P) O Scheme 5.9 Although 1-vinylnaphthalene thermally reacts with 4-acetoxy-2-cyclopenten1-one (98) to regioselectively afford 99, the isomer 2-vinylnaphthalene gives the same thermal cycloaddition with low yield (30 %) and reacts satisfactorily only with 98 at 10 kbar (Scheme 5.10). Both products 99 and 101 were converted into the cyclopenta[a]phenanthren-15-one (100) and cyclopenta[c]phenanthren-1one (102) isomers. Acetoxyketone 98 acts as a synthetic equivalent of cyclopentadienone (114 in Scheme 5.14) in cycloaddition reactions [33]. High Pressure Diels±Alder Reaction 221 H H EtAlCl2, 0 ⬚C, 6 h, 75% O 10% Pd-C O 100 99 O 98 OAc H O O H 10% Pd-C EtAlCl2, 10 kbar 35 ⬚C, 14 h, 42% 101 102 Scheme 5.10 Since dihydroarylethenes are more reactive than the corresponding fully aromatic compounds, their use in the cycloaddition reactions is preferred in order to carry out the reactions under mild conditions with higher yields. Some reactions of 3,4-dihydro-1-vinylnaphthalene (103) [33], 3,4-dihydro-2-vinylnaphthalene (104) [34], and 1,2-dihydro-4-vinylphenanthrene (105) [35] with 4-acetoxy-2-cyclopentenone (98) and 2-inden-1-one (106) are summarized in Schemes 5.11±5.13. O H H + 98 OAc A or B HH HH O 107 108 A: EtAlCl2, 0 ⬚C, 75%, 107/108 = 1 B: 10 kbar, 35 ⬚C, 68%, 107/108 = 6 103 H 10 kbar, 35 ⬚C 14 h, 60% HH 106 O Scheme 5.11 O O 222 Inner-Outer-Ring Dienes O H O H H 10 kbar, 35 ⬚C 98 OAc 66 h, 70% O 104 H 7 kbar, 50 ⬚C 3 h, 70% H H H O + H 106 O Scheme 5.12 A or B 10% Pd-C 56% O O O A: DCM, 0 ⬚C, 2.5 h, 75% one stereoisomer B: 9 kbar, DCM, 30 ⬚C, 17 h, 74% two stereoisomers 98 OAc 105 O 106 O 1. 7 kbar, DCM 35 ⬚C, 6 h, 43% + 2. 10% Pd-C 53% O 109 110 109/110 = 3.5 Scheme 5.13 High Pressure Diels±Alder Reaction 223 Pressure influences the regioselectivity and the endo±exo diastereoselectivity of the cycloadditions. All the cycloadducts were converted into polycyclic aromatic hydrocarbons by treatment over a Pd/charcoal catalyst. This approach provides a new and efficient route to a broad variety of polycyclic aromatic hydrocarbons [36]. When electron-withdrawing groups are introduced at the vinyl moiety, arylethenes may behave as dienophiles. Thus a-trifluoromethyl styrene (111) interacted with Danishefsky's diene (12b) under thermal or high pressure conditions [37] to regioselectively afford a 1:1 mixture of cycloadducts which were then converted to 4-phenyl-4-trifluoromethyl-2-cyclohexen-1-one (112) (Equation 5.12). A direct access to angularly trifluoromethyl-substituted tricyclic compounds may be achieved by cycloaddition of the 1-trifluoromethyl-3,4-dihydronaphthalene (113) with diene 12b (Equation 5.13). OSMT Ph F3C + or 15 kbar, 80% OMe 111 80% F3C Ph OMe O OMe CF3 15 kbar, 50 ⬚C 66 h OMe 113 5:12 F3C Ph 112 OSMT + 5.5.1 H+ 12b CF3 5.5 OSMT 140 ⬚C, 75% F3C H+ TMSO H O 5:13 H 12b INNER-RING DIENES Cyclopentadienes and Cyclohexadienes 4-Acetoxy-2-cyclopenten-1-one (98) is an interesting dienophile that acts as a synthetic equivalent of cyclopentadienone (114) [38]. Ketone 98 is poorly reactive; whereas it underwent cycloaddition reactions with reactive cyclic dienes, such as cyclopentadiene (115a) using zinc chloride as catalyst, it did not react with less reactive dienes such as 1,3-cyclohexadiene (115b) and 2,3-dimethyl1,3-butadiene (51). At 12 kbar and using zinc chloride as catalyst, both dienes underwent a smooth reaction (Scheme 5.14) [39]. Treatment of the reaction mixtures with 1n KOH afforded endo-tricyclo [5.2.2.0[2,6]] undecadienone (116a) and dimethyl tetrahydroindenone (116b), in 72 % and 58 % overall yield, respectively; these are suitable synthons for a variety of natural products. 224 Inner-Ring Dienes H H 116b O 1. 12 kbar, ZnCl2, 58% 2. KOH O H H 115b 1. 12 kbar, ZnCl2, 72% 2. KOH 98 OAc O 116a 51 115a 1. 12 kbar, ZnCl2, 19 h, 95% 2. KOH H H O O 114 Scheme 5.14 An interesting phenomenon has been observed in the high pressure Diels± Alder reactions of the 1-oxa[4.4.4]propella-5,7-diene (117) with 1,4-naphthoquinone, maleic anhydride and N-phenylmaleimide, where the diene 117 undergoes a rearrangement to the diene isomer 118 which, although thermodynamically less favored, exhibits a greater reactivity [40]. The reactivities of the three dienophiles differed since maleic anhydride and N-phenylmaleimide reacted only in the presence of diisopropylethylamine (DIEA) and camphorsulfonic acid (CSA), respectively (Scheme 5.15). The distribution of the adduct pairs shows that the oxygen atom does not exert a consistent oriental dominance on -facial selectivity. Cycloalkenones and/or their derivatives can also behave as dienic partners in the Diels±Alder cycloaddition. It is well documented [41] that cyclic acetals, for example, can interconvert with ring-opened enol ether forms, in a reversible manner; the latter compounds can then be trapped by various dienophiles. Thus dienes 119 and 120 reacted with [60]-fullerene (C60 ) at high pressure, affording highly thermally stable products [42] (Scheme 5.16). Ketones 123 and 124 could be directly obtained by cycloaddition of enol forms 121 and 122 of 2-cyclopenten-and 2-cyclohexen-1-one, respectively. High Pressure Diels±Alder Reaction 225 O 117 O O O H O H O H O N Ph H N Ph O + O 1:1 H CSA, 20 kbar, DCM, 4 d, 52% O O + 118 O H O H N Ph O H O H O DIEA, 20 kbar, DCM, 7 d, 53% O 1.5:1 20 kbar, DCM, 14 d, 27% O O O O O H O O H O H O + H O O 1:1.7 O Scheme 5.15 O O n OH O C60 n n O 3 kbar, 130 ⬚C 24 h, 82−85% C60 O n = 1 119 n = 2 120 H+ O OH n C60 n n 121 122 3 kbar, 130 ⬚C 71−81% n = 1, 2 Scheme 5.16 C60 O 123 124 226 5.5.2 Inner-Ring Dienes Tropones as Dienes Tropones are non-benzenoid compounds that behave like 4-components in a Diels±Alder reaction. These compounds are of interest because of their synthetic applications based on the Diels±Alder reaction, since the cycloadducts can be easily converted into a large variety of compounds. The study of high pressure cycloaddition reactions of tropone (125) with maleic anhydride and norbornene allowed the reaction activation volumes to be measured and showed that they are large, negative and solvent-dependent (Scheme 5.17) [43a]. O O O O H HO ∆V (IPB)= −21.4 cm3 mol−1 ∆V (DMF)= −16.8 cm3 mol−1 O O O 125 O H H ∆V (IPB)= −30.0 cm3 mol−1 ∆V (DMF)= −27.8 cm3 mol−1 Scheme 5.17 Tropone (125) and the 2-substituted tropones showed a different reactivity in the cycloaddition with 2-cyclopentenone (28). Whereas tropone itself (125) and the 2-methoxytropone (126) reacted at 10 kbar, giving a mixture of four and three products, respectively (Scheme 5.18), 2-hydroxy- and 2-chloro-tropone failed to react at all [43b]. Compound 127 does not have the expected dihydrohomobarrelenone framework; it is probably derived from the cycloaddition of 125 and 1,4-cyclopentadien-1-ol, the enol form of 28. Similar results were obtained in the cycloadditions of 2-cyclopentenone 28 with 2-methoxy-4-isopropyl-tropone (128) and 2-methoxy-6-isopropyl-tropone (129) (Equations 5.14 and 5.15). Tropone (125) and tropolone (130) reacted [44] with N-phenylmaleimide at high pressure (10 kbar) and gave a mixture of exo- and endo-adducts, 131 and 132, respectively (Equation 5.16). Another versatile two-step synthesis of homobarrelenones [45] is based on the high pressure cycloaddition of tropone (125) and its 2-methoxy-, 2-hydroxy- and 2-chloro-derivatives with 2,3-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hepta 2,5-diene (133) followed by thermolysis of the cycloadducts at 130 8C with the High Pressure Diels±Alder Reaction 227 O R H H O O + O R R O H 10 kbar, PhMe + O H 100 ⬚C, 10 h, 20% R R=H 125 R=OMe 126 28 O O H HO O + 127 Scheme 5.18 O OMe 10 kbar, PhMe + MeO O OMe H HO O 150 ⬚C, 30 h, 61% O + H H 5:14 O 128 28 O O OMe + 129 10 kbar, PhMe 150 ⬚C, 30 h, 67% O OMe H HO O OMe H H + + 28 O R + O O 5:15 H O Ph N O R H H O O 10 kbar O R= H 125 R= OH 130 MeO 131 N H O R O N Ph + H Ph O H O 5:16 132 extrusion of the furan ring (Equation 5.17). Diels±Alder adducts of furans are known to readily undergo a cycloreversion reaction; 7-oxabicyclo[2.2.1]heptadiene 133 behaves like a synthetic equivalent of acetylene [46]. Homobarrelenones substituted at the bridgehead carbon rearrange into the indanones. 228 Inner-Ring Dienes R O O R CO2Me + CO2Me O R 1. 3 kbar, PhCl, 100−130 ⬚C, 12 h O + 2. 120−130 ⬚C CO2Me MeO2C 5:17 + O 133 R = H, OMe, OH, Cl Tropone (125) reacted with acrylonitrile under both thermal and high pressure conditions [47] to afford a mixture of regioisomers and endo±exo diastereoisomers (Scheme 5.19). The product distribution was not dependent on pressure, but was slightly temperature dependent. There is a sharp preference for endo-selectivity. Cycloaddition of 125 with buckminsterfullerene (C60 ) at 3 kbar allowed the adduct [48] to be obtained, preventing a retro Diels±Alder process (Scheme 5.19). Cycloadditions of tropone (125) with furans 134 gave mixtures of 1:1 endo-and exo-monocycloadducts 135 and 136, respectively [49a], together with some bisadducts. In this case furan reacts solely as the 2 component in spite of its diene system. Whereas 2-methoxy furan gave mainly the kinetically controlled product 135 (R= OMe; R1 R2 H), under the same conditions 3,4dimethoxy furan afforded the thermodynamically controlled cycloadduct 136 (RH; R1 R2 OMe) as the major product (Scheme 5.19). O O + CN O + O CN + CN CN CH2=CH2CN O O R2 R 6−10 kbar DCM or PhMe R1 R2 O R1 O 134 135 C60 3 kbar, PhMe 3 kbar 11−36% O H R2O O R 125 R, R1, R2 = H, OMe R R1 136 Scheme 5.19 C60 High Pressure Diels±Alder Reaction 229 Azulene quinones [49b] are compounds related to the family of tropones and are considered to possess great biological and physiological potential. Several polycyclic compounds have been prepared by high pressure (3 kbar, PhCl, 130 8C, 15 h) Diels±Alder reaction of 3-bromo-1,5-azulene quinone (137) and 3-bromo-1,7-azulene quinone (138) with several dienophiles. The cycloadditions were regioselective and afforded cycloadducts in reasonable to good yields (Scheme 5.20). Br O Br N-Ph O R Br O O HO R-CH=CH2; (R=Ph, CN) O 70% + 48-77% O O O O N-Ph O Br O 137 R H O O O O O N-Ph Br HO O O O 44% N-Ph Br O R R-CH=CH2; (R=Ph, CN) + 44-63% Br 138 O O Br R H Scheme 5.20 5.5.3 Furans and Thiophenes Heteroaromatic five-membered compounds, such as furan (139a) and thiophene (139b), may be formally considered to be 1,3-butadienes with their terminal carbons `tied down' by a heteroatom bridge; chemically, they can behave as conjugated dienes. Furan (139a) has a low aromatic character and hence it has a great tendency to behave like a conjugated diene. Unlike furan, the more aromatic thiophene (139b) is a very poor diene that does not usually undergo the Diels±Alder reaction under thermal and Lewis-acid-catalyzed conditions. It may react with highly reactive dienophiles like dicyanoacetylene and tetrafluorobenzyne to give aromatic compounds; the Diels±Alder cycloadditions of thiophenes are often followed by the loss of the heteroatom. The thiophene derivatives, such 230 Inner-Ring Dienes as thiophene-1,1-dioxide and 2,5-dimethoxythiophene, react thermally. However, the reaction of thiophene (139b) with maleic anhydride may be promoted by high pressure [50] and leads to the exo-cycloadduct, with the yield depending on the reaction temperature, pressure and solvent (Equation 5.18). Under high pressure conditions, the choice of solvent becomes important as is well documented in various studies on the kinetic solvent effects [51]. The best yield was obtained at 100 8C and 20 kbar in dichloromethane. O S + O O 3 h, 47% 5:18 H H O O 139b O S 20 kbar, DCM, 100 ⬚C The more reactive furan (139a) undergoes thermal Diels±Alder reaction [52] with reactive dienophiles such as maleic anhydride and maleimide (Scheme 5.21). Whereas the cycloaddition with the maleic anhydride afforded the exoadduct at room temperature, the stereochemistry of the reaction of maleimide depends on the reaction temperature. Diels±Alder reactions of furans are markedly reversible because of the aromatic character of the furan nucleus [1a]. The lability of the cycloadducts, even at relatively low temperatures, as well as the sensitivity to acidic conditions of both furans and cycloadducts, preclude the use of strong Lewis acids and have therefore given importance to the high pressure technique. O O O H H O O O O O H 141 O MeCN r.t. O O O O H O O 90 ⬚C NH NH H H O O O H2, Pd/C, 99% O O O O 139a O 25 ⬚C O 140 8 kbar, 4 d, 97% H H O O O Scheme 5.21 NH High Pressure Diels±Alder Reaction 231 Whereas maleic anhydride can react with furan (139a) at ambient pressure, citraconic anhydride (140) reacts only at high pressures due to the strong deactivating effect of the methyl group (Schemes 5.21 and 5.22). The two-step synthesis [53] of the palasonin (141), in an overall yield of 96 %, is a good example of the acceleration of the Diels±Alder by high pressure (Scheme 5.21). Previous synthesis [54] based on the thermal Diels±Alder reaction of furan with methoxy carbonyl maleic anhydride required 12 steps. High pressure cycloaddition of cytraconic anhydride (140) with 2-substituted furans 142 afforded, exo-diastereoselectively but unregioselectively, bicyclic cycloadducts 143 and 144 that have been used in straightforward routes to CD-ring fragment of paclitaxel [55] (Scheme 5.22). The cycloadducts were then O O + O 142 + 60 h O 140 O R O H 143 R Me CO2Et CH2OAc CH2OCOt-Bu CH2OBn O O O R R O O DCM, 15 kbar H O 144 143/144 Yield (%) 1 ± 0.8 1 1.4 65 ± 59 54 31 Scheme 5.22 converted into bicyclic lactones 145 and 146 and into cyclohexene derivative 147 (Figure 5.3) which is a potential precursor in the total synthesis of paclitaxel and paclitaxel analogs. The application of high pressure accelerates the formation of cycloadducts 143 and 144. AcO O HO O AcO CO2Me O O Figure 5.3 H H 145 146 CO2Me 147 232 Inner-Ring Dienes Diels±Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropholone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57]. Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5 kbar of pressure to a neat 1:1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded ()-jatropholones 151 and 152. O OMe OMe 5 kbar, 72 h + O HH 80% O H H O H (−) 149 148 H 150 OH OH H H O O H (+) 151 H (+) 152 Scheme 5.23 High pressure technique has also been applied successfully to intramolecular Diels±Alder reactions of furan derivatives. Furfuryl-substituted methylene cyclopropane derivatives 153 did not undergo intramolecular cycloaddition under thermal conditions, since tar and polymers were essentially obtained. Lewis-acids, such as Cu OAc2 H2 O, ZnI2 , LiClO4 and BF3 OEt2 , which have been reported to promote cycloaddition reactions of furan derivatives, failed or were only marginally successful. At high pressure, compounds 153 underwent intramolecular Diels±Alder reaction [58] readily and exo-diastereoselectively, leading to new spirocyclopropane tricyclic compounds 154 in good to high yields (Scheme 5.24). In order to quantify the pressure effect on the kinetics, the activation volumes were determined. High Pressure Diels±Alder Reaction 233 R R1 R O X O 10 kBar, MeCN-THF R1 60-70 ⬚C, 20-42 h H R1 X R1 153 154 X R R1 Yield(%) O O O O NMe NMe H H Me OMe H H H Me H H H =O >95 >95 74 >95 50 55 Scheme 5.24 The synthesis of phorbols [59] is another representative example of high pressure intramolecular Diels±Alder reaction. Phorbol 155 is a natural product found in croton tiglium oil. Phorbols are biologically active diterpene members of the tiglione family which have a tetracyclic framework. Prostatin 156 (12-deoxyphorbol acetate) is of medical interest due to its cytoprotective effect in human lymphocytic cells infected with HIV-1. A one-pot stereocontrolled construction of the base tricyclic skeleton, having the functionality and stereochemistry inherent in phorbols and its analogs, has been achieved by high pressure mediated intramolecular cycloaddition of compounds having the furane moiety (Scheme 5.25). OH OAc OH H H OH OH HH HH O HO O HO OH OH 155 156 R H R O O 19 kbar, DMC 17 h, 45% O O O H O O OH CO2Me 158 157 a, R = SBn b, R = SPh Scheme 5.25 CO2Me 234 Inner-Ring Dienes Furan derivative 157a at 19 kbar gave the tricyclic product 158 endo-diastereoselectively and in good yield. Disconcertingly, it was found that analog 157b did not react, thus emphasizing that the nature of the thioether group at the furan nucleus plays a crucial role in the success of the intramolecular process. While the real reason for the reluctance of compound 157b to undergo cycloaddition remains obscure, the fact that the Diels±Alder reaction is possible with substrate 157a has opened a route to the total synthesis of phorbol. Fused norbornene analogs, containing silicon and oxygen atoms in bridgehead positions, have been prepared [60] by high pressure cycloaddition of siloles 159 and 160 with oxanorbornene derivatives 161±164 (Scheme 5.26). These cycloaddition reactions at atmospheric pressure either do not proceed or proceed only at higher temperatures where the starting materials already begin to thermally decompose. The cycloadducts are cavity-shaped silicon-containing polycyclic systems of potential interest for host±guest chemistry. Ph Ph Si Ph Ph 159 Ph Si H H 161 H H O O O 162 O 160 H H O O Ph 163 H H O O 164 Scheme 5.26 5.5.4 Pyrones and Pyridones Whereas electronically activated 2-pyrones can react thermally in both normal and inverse electron-demand Diels±Alder cycloaddition, 2-pyrone by itself requires thermal conditions that are so vigorous that they cause spontaneous extrusion of carbon dioxide from the bicyclic cycloadduct [61]. High Pressure Diels±Alder Reaction 235 Synthon 168, a direct precursor to ring-A diastereoisomer of 1-hydroxyvitamin D3 analog having selective biological activities, has been synthesized by high-pressure Lewis-acid-catalyzed inverse electron-demand Diels±Alder cycloaddition of the commercially available 2-pyrone (165) with benzylvinylether (166) [62]. The cycloaddition led regio-and diastereoselectively to bicyclic lactone 167 which was then converted, by methanolysis, to the trisubstituted cyclohexene 168 (Equation 5.19). No cycloaddition occurred at atmospheric pressure or under the influence of the Lewis acid alone, and only low cycloadduct yields were obtained when performing the reaction under high pressure without a Lewis-acid catalyst. O O + O Bn Yb(tfc)3, 12 kbar r.t., 3 d, 91% 165 166 O CO2Me OBn MeOLi O H HO OBn H 167 5:19 168 A marked dependence of the reaction yield on the nature of the Lewis-acid catalyst and on the diene±dienophile ratio was observed (Table 5.4). 2-Pyrone (165) reacted at 18.5 kbar with methylacrylate but the reaction was unregioselective and undiastereoselective. 2-Acetoxypyran-2-one (169) reacted with chiral enolethers 170 under high pressure conditions. Diastereofacial selectivities ranged from 52/48 to 88/12 depending on the nature of the dienophile [63] (Equation 5.20). Table 5.4 High pressure Lewis-acid catalyzed Diels±Alder reactions of 2-pyrone 165 with benzylvinylether 166a Lewis-acid Yb tfc3 (homochiral) Yb fod3 Yb fod3 Yb NO3 3 5H2 O Yb NO3 3 5H2 O ZnCl2 ZnCl2 ZnCl2 a b In the absence of solvent. In DCM at 11±12 kbar. 166 (equiv.) Yield (%) 2 2 5 2 5 2 5 5 91 72 94 31 90 24 73 92b 236 Inner-Ring Dienes O OAc OR* O 13 kbar, 25 ⬚C + O OAc DCM, 7 d, 60−75% O 5:20 OR* 169 170 171 R* = isomenthyl; 2-(a-naphthyl)cyclohexyl; 8-phenylmenthyl; 8-(b-naphthyl)menthyl; 8-(3,5-dimethylphenyl)menthyl. 2-Pyridones have higher aromatic character than 2-pyrones and therefore give Diels±Alder cycloadditions at atmospheric pressure with highly reactive dienophiles or when electron-withdrawing substituents are present in the molecule. The reactions of some phenyl-substituted 1-methyl-2(1H)-pyridones 172 with N-phenylmaleimide under atmospheric and high pressure conditions have been examined in order to open a new efficient route towards isoquinuclidine derivatives [64]. High pressure cycloadditions afforded high yields of mixtures of endo and exo adducts 173 and 174, some of which were unobtainable under atmospheric pressure. The endo±exo diastereoselectivity is influenced by the pressure (Scheme 5.27). R4 Me N O Ph N O + O Me O 10 kbar, PhMe 110 ⬚C R1 R3 R2 N R3 R4 O R2 O R1 H H O Yield (%) at 10 kbar + R2 R4 Ph R1 H Yield (%) at 1 atm R2 R3 R4 173 174 173 174 Ph H H H H Ph H H H H Ph H H H H Ph 26 11 78 76 50 2 18 8 0 50 90 0 0 0 0 0 O N Ph HO 174 R1 Scheme 5.27 N R3 N 173 172 Me High Pressure Diels±Alder Reaction 5.6 237 OUTLINED DIELS±ALDER REACTIONS A simple entry towards bi-and tricyclic N-oxy-b-lactams by high pressure promoted tandem [4 2]/[3 2] cycloadditions of enol ethers and b-nitrostyrene [65] O RO N O RO O O N + Ph Ph 15 kbar DCM, 17 h H Ph Base - NO2 NO2 RO O O N RO O Ph Ph Ph RO N O H Ph O N O + NO2 Ph R = Me, Et H NO2 Ph Yield = 63-90% A versatile synthesis of substituted tetrahydropyridines [66] R1 CCl3 CCl3 + R2 N 12 kbar, DCM N 70 ⬚C, 36 h Ts R1 8 examples Ts R2 Yield = 60-91% The preparation of rigid alicyclic molecules bearing effector groups from alkene blocks using s-tetrazines and 1,3,4-triazines as stereoselective coupling agents [67] Py Py N N + N N Py 5 dienophiles Et3N DCM, r. t., 2 h H H Py O N N N Yield = 54-91% N 14 kbar Py Py O 238 Outlined Diels±Alder Reactions High-pressure cycloaddition reactions of 3-bromo-1,5-azulenequinone and 3-bromo1,7-azulenequinone with dienophiles [68] Br O O + Br O 3 kbar, PhCl N-Ph 130 O H ⬚C N O O O Ph O 9 dienophiles Yield = 17-80% O Br O + O O 3 kbar, PhCl N-Ph 130 Br H ⬚C N O O O Ph O 5 dienophiles Yield = 44-64% Asymmetric hetero-Diels±Alder addition of 1-methoxybuta-1,3-diene to (2R)-N-pyruvoyl-and (2R)-N-(phenylglyoxyloyl)bornane-10,2-sultam [69] OMe O O 14 kbar, DCM + R N SO2 N 50 ⬚C, 48 h, 86% Me R O O O + N R = Me R = Ph 34% 37% 66% 63% LiAlH4 THF R HO O SO2 SO2 O Me R O LiAlH4 THF R OMe HO O OMe Synthesis and structure-activity data of some new epibatidine analogues [70] CO2Me CO2Me SO2Ph N + CO2Me N 6% Na(Hg) 12 kbar, MeCN 50 ⬚C, >95% SO2Ph endo /exo = 1:1 30% N O High Pressure Diels±Alder Reaction 239 Synthesis of tetrahydro-and dihydropyridines by hetero-Diels±Alder reaction of enantiopure a,b-unsaturated sulfinimines [71] Ph R R CN + R1 R2 R 11 kbar, r.t., 48 h S Tol CN R DCM N Ph R1 R2 O N S Tol O (+) R = H, Me; R1 = OEt, SPh, Ot-Bu, SMe, OMe, Me; R2 = H, Me, SMe Yield = 0-99% Improved synthesis of 1,4-phenanthrenequinones from Diels±Alder cycloadditions of 2-(p-tolylsulfinyl)-1,4-benzoquinone [72] O O SOTol 12.5 kbar, DCM + 20 ⬚C, 96 h, 55% O O 9 examples Yield = 19-80% Regiocontrolled and stereocontrolled Diels±Alder cycloadditions of 2-pyrones and unactivated unbranched 1-alkenes [73] O R R1 O + O R1 ZnX2 (X = Cl, Br), 10-12 kbar O H DCM, 25 ˚C, 3-5 d H R H R = n-Pr, CH2Si(OEt)3, CH2CH2OSBT, CH2CH2OBn, CH2OSBT; R1 = Br, CO2Me Yield 64-80% High-pressure and thermally induced intramolecular Diels±Alder reactions of furfuryl fumarates. Influence of tether substituents on diastereoselectivity [74] H OMe OO O O R H O H + H CO2Me MeO2C OH O O HO R O 7 kbar, 18 h Acetone, 40 ⬚C R H H H (−) R = Me, Et, i-Pr, t-Bu, neo-Pn, Ph Yield = 36-96% d.e. = 10-86% 240 Outlined Diels±Alder Reactions Intramolecular Diels±Alder reaction of chiral highly oxygenated trienoates derived from sugar allyltins [75] CO2Me MeO2C 15 kbar, PhMe, 50 CbzO OCbz H ⬚C OCbz 24 h, 70-80% OCbz H OCbz OCbz 3 examples (S,S)-1,1-Bis-ethoxycarbonyl-2,2-bis-p-tolylsulfinyl ethene: a highly diastereoselective but unexpectedly unreactive dienophile in asymmetric Diels±Alder reactions [76] TolOS SOTol 13 kbar, DCM r.t., 24 h, 72% + EtO2C CO2Et (S,S) (+) 4 examples SOTol SOTol + CO2Et CO2Et 87% CO2Et CO2Et SOTol SOTol 13% Yield = 10-82% Intermolecular hetero-Diels±Alder reactions of enamino ketones with highly substituted vinyl ethers. Effect of high pressure on the kinetics and diastereoselectivity [77] NPht NPht + O O X3C O X3C NPht 0.25-3.0 kbar, DCM + O O X3C O O X = F, Cl Pht = 5 examples Yield = 48-95% O Diels±Alder reaction of the dihydropyridinones. V: Approach to the ircinal B core [78] H CN PhO2S OMe 1. 15 kbar, PhMe r.t., 4 d, 66% PhO S N 2 2. CSA + N O OSMT O CN O 66 % High Pressure Diels±Alder Reaction 241 Facile synthesis of optically active trifluoromethylated compounds: asymmetric Diels± Alder reaction of trifluoromethylated a,b-unsaturated sulfonamide under high-pressure conditions [79] F3C O Ph R= CF3 10 kbar, PhMe 40 ⬚C, 14 h SO2R + O O N SO2R + SO2R CF3 Ph 5 dienes O Yield = 40-75% The high pressure Diels±Alder reactions of quinone-mono-ketals [80] O O R 13 kbar, DCM 2 d, 86% + R1 MeO R R R1 H MeO OMe OMe R = Et, R1 = H ; R = H, R1 = Me OH H R1 OMe Yield = 31-96% Exohedral functionalization of [60]-fullerene by [42] cycloadditions. Diels±Alder reactions of [60]-fullerene with electron-rich 2,3-dioxy-substituted-1,3-butadienes [81] O C60 + 3 kbar, C6H4Cl2 O 24 h O O TFA C60 O C60 HO 33% overall yield High-pressure and thermally induced asymmetric Diels±Alder cycloadditions of heterosubstituted dienes to homochiral a,b-didehydro amino acid derivatives [82] Ph O O N O 12.5 kbar, DCM r.t., 6 h, 91% TMSO HO Ph OSMT H CO2Me 14 kbar, DCM 60 ⬚C, 120 h, 70% NHCbz TMSO CO2Me H H TMSO NHCbz NHCbz CO2Me CO2Me H + O O O NHCbz O TMSO O N H O O O major H + O O O O minor 242 Outlined Diels±Alder Reactions Synthesis of highly functionalized 3,4-dihydro-2H-pyrans by high-pressure Lewis-acidcatalyzed cycloaddition of enol ethers and a,b-unsaturated aldehydes [83] H O H O OR1 R2 R3 O O R1O Ln cat:, 15 kbar, r.t., 16-72 h, 65-85% R2 R3 Ln cat:, 15 kbar, 50 ⬚C, 72 h, 36-37% OR1 R2 R3 R1 = Et, R2 = Me, R3 = Me R1 = i-Pr, R2 = Me, R3 = H Synthesis of sterically rigid macrocycles by the use of pressure-induced repetitive Diels±Alder reactions [84] OMe H H OMe H H OMe PhMe, 125 ⬚C, 8 kbar, 4 d, 60 % OMe OMe H H H MeO H H OMe H H H MeO High Pressure Diels±Alder Reaction 243 The first example of an increase in the enantioselectivity of a chemical reaction in the presence of a chiral Lewis acid under high pressure [85] Ph OMe O Ph Me O O O O Ph N Ph O OMe TiCl2 O Ph H N 1-5 kbar, DCM, r.t., 81-95 % O O N O O O N ee = 4.5 (1 bar) ee = 20.4 (5 kbar) Synthesis and high-pressure Diels±Alder cycloadditions of 6-methoxycarbonyl-3-oxo2-azabicyclo[2.2.0]hex-5-ene [86] H H O MeO2C + NH 10 kbar, DCM 50 ⬚C, 24 h, 73 % O O O NH MeO2C H 4 dienes Yield: 70-88 % High-pressure organic chemistry. Part 17. Diels±Alder reaction of methyl palustrate with maleic anhydride and N-phenylmaleimide [87] O O O H H Ph O N O H H CO2Me H O O N Ph O O 10 kbar, DCM 80 ⬚C, 48 h, 68% O H CO2Me H CO2Me + 10 kbar, DCM 85 ⬚C, 70 h, 27% H O O H CO2Me O 244 Outlined Diels±Alder Reactions Diastereoselective Diels±Alder reactions with chiral sulfinyl derivatives as dienophiles under high pressure [88] O2N NO2 O− Ph S+ (S) 8 kbar, DCM r.t., 5 d, 80% + −O S+ Ph 3 dienophiles, 5 dienes, Yield = 39-81 % Studies on Diels±Alder reactions of 1,3,3-trimethyl-2-vinylcyclohexene with 2-cyclohexenones [89] O E O E H + ZnBr2, 12 kbar, DCM, 23 h, 65% E O OH major E = CO2Me O O ZnBr2, 12 kbar, DCM, 23 h O O H O O O O O + E E + E O O HO E major Total synthesis of ()-erysotrine via asymmetric Diels±Alder reaction under super high pressure [90] H MeO N MeO O 1. 10 kbar, DCM 40-50% OSMT + O MeO2C O H MeO CO2Me Me N MeO 2. SiO2 O CO2Me O O CO2Me OMe High Pressure Diels±Alder Reaction 245 High-pressure [4 2] cycloaddition of 1-methoxy-1,3-butadiene to N,O-protected D -threoninals and D-allo-threoninals [91] NHCbz NHCbz + H Ether, 50 ⬚C, 24 h O OMe NHCbz Eu(fod)3, 15 kbar O H + OBOM H O OBOM OBOM OMe OMe 4 dienophiles Double Diels±Alder cycloadditions of 2-(1H)-pyridones acting as dienophiles [92] + O N R H H 10 kbar, PhMe 80 ⬚C, 96 h O N R O R = H, Me H O Yield = 11-19% 5,6,7,8-Tetramethylenebicyclo[2.2.2]oct-2-ene as `bisdiene' in repetitive Diels±Alder reactions [93] H H O O O H H + 7.5 kbar, DCM 50 ⬚C, 2 d, 56% H H H H O O 7.5 kbar, DCM 55 ⬚C, 3 d, 85% O O H H H H O O O O High-pressure Diels±Alder reaction of 1-methyl-2-(1H)-pyridones having a phenyl group with N-phenylmaleimide [94] O R1 O R R2 + R3 N N Ph O 10 kbar, PhMe R1 R ⬚ 110 C, 3 d, 13-96% 2 O R = R1 = R2 = R3 = H, Ph N R3 O O N R H O R + N Ph 1 H R2 N H Ph R3 H O O R endo/exo = 0.5−9.5 246 References REFERENCES 1. 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The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 6 Diels±Alder Reaction in Unconventional Reaction Media The idea that the reaction medium is a passive medium in which the dissolved material simply diffuses has been abandoned and chemists now realize that the reaction medium can greatly influence both the reactivity and selectivity of a process [1]. The choice of reaction medium is important and the most important criteria that must be complied with are (i) unreactivity towards reactants and products, (ii) a large range between the melting and boiling points, (iii) good chemical and thermal stability, (iv) compatibility with the analytical methods used to test the reaction, and (v) good solubility of the reactants, and sometimes of products, even if excellent results can be obtained in the heterogeneous phase. Additional parameters must be considered for a reaction medium used for industrial purposes, such as price, explosiveness, inflammability, viscosity, toxicity, corrosiveness and recyclability. Organic solvents have been the commonly used reaction medium in organic reactions, but during the last 20 years (in part stimulated by problems connected with environmentally sustainable growth) new reaction media have emerged which have given surprising and exceptional results. Water, lithium salts in diethyl ether and nitromethane, ethylene glycol, phenols, ionic liquids, microemulsions and supercritical fluids are those that have given the best results. 6.1 DIELS±ALDER REACTION IN AQUEOUS MEDIUM In 1980, organic chemists recognized the potential of the aqueous medium as a reaction medium when Breslow [2] showed that some Diels±Alder reactions were strongly accelerated when carried out in water in comparison with the same reactions performed in organic solvent. Interest in the aqueous medium spread quickly and many, sometimes surprising, discoveries were made [3]. Today pericyclic [4], condensation [5], oxidation [6] and reduction [7] reactions are routinely carried out in aqueous medium. The recent discovery of water-tolerant Lewis acids such as lanthanide triflates, Bi OTf3 , Sc OTf3 and Y OTf3 has revolutionized organometallic chemistry [5a, 7]. The aqueous medium offers notable advantages with respect to organic solvents: (i) it is abundant, cheap, non-toxic and environmentally friendly, (ii) 252 Diels±Alder Reaction in Aqueous Medium inflammable solvents are not handled, (iii) the reaction products can sometimes be isolated simply by decantation or filtration, (iv) the protection±deprotection of certain functional groups (OH, COOH) may be unnecessary, (v) watersoluble compounds can be used directly without derivatization, (vi) salts, surfactants and cyclodextrins can be used, and (vii) the pH can be carefully controlled, which allows the reactivity and selectivity of the reaction to be strongly influenced [8]. Aqueous medium does not mean water only but also includes homogeneous mixtures of water and organic solvents (mainly THF, EtOH, MeOH and MeCN). The reaction can be carried out in either the homogeneous or the heterogeneous phase. The use of cosolvents and salting-in agents (guanidinium chloride, LiClO4 ) allows the reaction to occur in the homogeneous phase but this may not favor the reactivity and selectivity of the process. Water has physical±chemical properties that are very different from those of other solvents [1] and its role in enhancing the reactivity and selectivity of some organic reactions is still a debated question. Recent experimental studies [3e, 9] and computer simulations [10] seem to indicate, at least with respect to the rate enhancement of aqueous Diels±Alder reactions, that the main effects are due to the enforced hydrophobic interactions and hydrogen bond interactions. Among the organic reactions that have been investigated in aqueous medium, the Diels±Alder cycloaddition has been the most studied owing to its great importance from the synthetic and theoretical point of view [7a, b]. In this section Diels±Alder reactions carried out in water under conventional conditions of temperature and pressure will be illustrated. The use of water at supercritical or near-supercritical conditions will be discussed in Section 6.4. 6.1.1 Uncatalyzed Diels±Alder Reaction The cycloaddition between furan and maleic anhydride was the first uncatalyzed aqueous Diels±Alder reaction reported in the literature and was studied by Diels and Alder themselves [11]. This cycloaddition was successfully revised by Woodward and Baer [12] and some years later by De Koning and coworkers [13]. The aqueous medium was also used in the cycloaddition of aromatic diazonium salts with methylsubstituted 1,3-butadienes [14]. Rideout and Breslow first reported [2a] the kinetic data for the accelerating effect of water, for the Diels±Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile and the cycloaddition of anthracene-9-carbinol with N-ethylmaleimide, giving impetus to research in this area (Table 6.1). The reaction in water is 28 to 740 times faster than in the apolar hydrocarbon isooctane. By adding lithium chloride (salting-out agent) the reaction rate increases 2.5 times further, while the presence of guanidinium chloride decreases it. The authors suggested that this exceptional effect of water is the result of a combination of two factors: the polarity of the medium and the Diels±Alder Reaction in Unconventional Reaction Media 253 Table 6.1 Relative reaction rates of Diels±Alder reactions in water and organic solvents krel ksolvent =kisooctane Reactants CH2OH + COMe + + CN O N O Et Reaction temperature and medium krel krel krel T (8C) Isooctane Methanol Water 20 1 13 740 20 1 2 31 45 1 0.43 28 hydrophobic interaction, namely the entropy-favored association of apolar groups or apolar molecules in water (hydrophobic packing of diene and dienophile). The effects of lithium chloride and guanidinium chloride support the idea of hydrophobic packing. The presence of lithium chloride increases the reaction rate because the salt makes the apolar reactants less soluble in water and in so doing it enhances the hydrophobic interaction. The guanidinium chloride has the opposite effect because the salt increases the solubility of apolar reagents in water, which decreases the hydrophobic interaction. The salt effect is also related to the ionic radius of the anion [15a]. Thus, the rate of the aqueous Diels±Alder reaction of anthracene-9-carbinol and N-ethylmaleimide decreases as the radius of the sodium salt anion increases and as the size of the guanidinium salt anion increases (Table 6.2). The internal pressure (a change in internal energy of water as a consequence of the very small thermal expansion), as altered by the salt, has also been suggested [15b] to be an important parameter in explaining the effect of salt in aqueous Diels±Alder reactions. Engberts [3e, 9] has extensively investigated the Diels±Alder reaction in aqueous medium. Recently Engberts and colleagues reported [9c] a kinetic study of a Diels±Alder reaction of N-alkyl maleimides with cyclopentadiene, 2,3-dimethyl1,3-butadiene and 1,3-cyclohexadiene in different solvents. The reaction rates of the cycloadditions with the open-chain diene relative to n-hexane are reported in Table 6.3. The aqueous medium greatly accelerates the Diels±Alder reaction and the acceleration increases as the hydrophobic character of the alkyl group of the dienophile increases. These and other kinetic data [3e, 9], along with the observation that the intramolecular Diels±Alder reaction is also accelerated in 254 Diels±Alder Reaction in Aqueous Medium Table 6.2 Sodium and guanidinium salt effects (relative reaction rates) of Diels±Alder reaction of anthracene-9-carbinol and N-ethylmaleimide O CH2OH N Et H2O + O N O O 45 ⬚C Et OH X NaX (krel ) C NH2 3 X(krel ) 1.00 1.34 1.30 0.98 Ð 0.89 0.83 0.78 1.00 0.56 0.50 0.40 0.38 0.37 Ð Ð None Cl Br BF4 SCN ClO4 PF6 AsF6 Ê) Ionic radii (A Ð 1.67 1.82 2.44 Ð 2.64 2.81 2.89 Table 6.3 Relative reaction rates of Diels±Alder reactions between 2,3dimethyl-1,3-butadiene and N-alkylmaleimides in different solvents at 25 8C (ksolvent =kn-hexane ) O + H N R O N R H O O krel Solvent C6 H14 MeCN EtOH PrOH TFE H2 O R Me Et Pr Bu 1 2.4 7.3 8.7 81 1000 1 2.4 7.0 8.0 76 1447 1 2.3 6.9 8.4 77 1683 1 2.0 6.1 8.8 80 1881 aqueous medium, have led to the proposal that the major factor that contributes to the rate enhancement of the Diels±Alder reaction in water is the enforced hydrophobic interactions and not the hydrophobic packing of the reactants. The term `enforced hydrophobic interactions' is used to emphasize that the hydrophobic interactions are an integral part of the activation process and contribute to stabilize the transition state relative to the initial state. A moderate acceleration can also be noted (Table 6.3) when the reaction is performed in Diels±Alder Reaction in Unconventional Reaction Media 255 1,1,1-trifluoroethanol (TFE), a solvent with a strong hydrogen-bond donor capacity. This supports the idea that hydrogen-bonding interactions also contribute noticeably to the acceleration of aqueous Diels±Alder reactions. The aqueous medium also has beneficial effects on the diastereoselectivity of the Diels±Alder reactions. The endo addition that occurs in the classical cycloadditions of cyclopentadiene with methyl vinyl ketone and methyl acrylate is more favored when the reaction is carried out in aqueous medium than when it is performed in organic solvents (Table 6.4) [2b, c]. The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a±c]. The key step of synthesis was the Diels±Alder reaction between the a,b-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R Na): when the reaction is conducted 2m in diene the reaction is complete in 5 h and the endo adduct is 75 % of the diastereoisomeric reaction mixture. The study was extended to other dienes and dienophiles [16d, e]. Some examples and comparisons are reported in Scheme 6.2. With respect to the organic solvent, the aqueous reaction requires milder conditions and the reactionis faster and more selective. It is significant that the use of cosolvents such as methanol, dioxane and tetrahydrofuran results in a reduction of reaction rate. Table 6.4 Endo/exo diastereoselectivity of Diels±Alder reactions in water and organic media COR + 20−25 ⬚C + COR COR (endo) (exo) Endo / Exo Medium R OMe R Me None (excess of diene) Isooctane Ethanol 1-Butanol Formamide N-Methylacetamide Water 74:26 69:31 84:16 83:17 87:13 82:18 90:10 79:21 89:11 96:14 256 Diels±Alder Reaction in Aqueous Medium HO OH O OH O H H H H O O Chaparrinone MeO CHO CHO r.t. + H O H 1 O H CO2R CHO + 14 H CO2R (endo) 2 O H CO2R (exo) R Medium t(h) endo/exo Yield (%) Et Et H H Na PhH H2 O PhMe H2 O H2 O 288 168 168 17 5 46:54 56:44 41:59 60:40 75:25 52 82 46 85 100 Scheme 6.1 O OMe O OMe MeO MeO + O O CO2R H CO2R R Medium t(min) T(8C) Yield(%) Me Na PhH H2 O 720 12 80 r.t. 69 93 AcO + MeO2C OAc AcO + MeO2C MeO2C CO2R CO2R CO2R (endo) (exo) R Medium t(h) T(8C) endo/exo yield(%) Me Na PhMe H2 O 96 24 110 60 33:66 67:33 84 67 Scheme 6.2 Diels±Alder Reaction in Unconventional Reaction Media 257 The nitroso moiety of the N-acylnitroso function is a powerful dienophile and therefore N-acylnitroso compounds are trapped rapidly, especially in an intramolecular reaction, with a diene allowing the Diels±Alder reaction to occur also in water, although N-acylnitroso compounds are short-lived in aqueous medium. N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homochiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0 8C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and trans-1,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCl3 solution, the reaction is poorly diastereoselective. In water, a considerable enhancement in favor of the trans adduct is observed. H Y N Y IO4 N OH O Y N O O O O 3 4 5 Y = R, OR, NR1R2 Scheme 6.3 OMOM OMOM H H MOMO NHOH 0 ⬚C, 1 min O N N O (trans) 7 6 + Medium trans/cis Yield (%) CHCl3 H2O 63:37 82:18 75 93 N O O O H H MOMO Pr4NIO4 O O (cis) Scheme 6.4 The acylnitroso approach has been used for the enantioselective syntheses of ( )-swainsonine and ( )-pumiliotoxin C [17d] (Scheme 6.5). 258 Diels±Alder Reaction in Aqueous Medium Lubineau and coworkers [18] have shown that glyoxal 8 (R1 R2 H), glyoxylic acid 8 (R1 H, R2 OH), pyruvic acid 8 (R1 Me, R2 OH) and pyruvaldehyde 8 (R1 H, R2 Me) give Diels±Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethylbutadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. OBn H OBn NaIO D-malic acid H2O, 0 ⬚C, 10 min, 85% NHOH O BnO Et acid N O Pr4NIO4 H2O, MeOH 0 ⬚C, 30 min, 84% NHOH O H N OH (−) swainsonine O OBn L-malic N OH OH H H Et O O N Et H (−) pumiliotoxin C H Scheme 6.5 O H2O + R1 COR2 O 100 ⬚C COR2 R1 8 O + 9 COR2 R1 10 R1 R2 t (h) 9/10 H OH 1.5 64:36 97 H Me 48 53:47 96 H H 60 50:50 36 Me OH 48 33:67 74 Yield (%) Scheme 6.6 These results have been used to prepare key starting compounds 11 and 12 for the enantioselective synthesis of 3-deoxy-d -manno-2-octulosonic acid Diels±Alder Reaction in Unconventional Reaction Media 259 (KDO) 13 [19a] and for a concise synthesis of ketodeoxyheptulosonic acid derivatives 14 [19b], respectively (Scheme 6.7). HO AcO HO 1. H2O 2. MeOH/H O + CO2Na H AcO O 3. Ac2O/Py 54 % CO2Me (endo-si + exo-si = 76 %) 11 HO OH O + CO2Na H 1. H2O, 100 ⬚C O + 2. H /CH2N2 CO2Me 12 HO OH HO HO OAc O O CO2H OH OH 13 (KDO) R1 AcO R2 R1 = CO2Me R2 = OMe R1 = OMe R2 = CO2Me 14 Scheme 6.7 Extensive work has been done by using buta-1,3-dienyl-glycosides of unprotected sugar to study aqueous Diels±Alder reactions and to prepare optically active oligosaccharides [20]. The cycloaddition of b-glucoside 15 (R1 R2 H) (Scheme 6.8) with methacrolein in water leads to a mixture of two endo adducts, the majority of which results from an approach of the dienophile part of glucoside to the re face of the diene as depicted in 16. A benzyl protecting group at O-6 (15; R1 Bn, R2 H) slows the reaction rate but does not influence the endo/exo diastereoselectivity or the face selectivity of the reaction (Scheme 6.8; 17). A reversal face selectivity occurs when the protecting group is at O-2 as illustrated in 18. The interaction between the phenyl ring and diene unit is enhanced by a hydrophobic interaction; the use of water therefore favors the packing and consequently the si approach. 260 Diels±Alder Reaction in Aqueous Medium OR1 6 HOHO O 2 CHO O + CHO S O S O CHO H2O OR2 15 (Endo-re) (Endo-si) S = b-D-glucose OH OH OH O HO HO O HO O 1 HO O HO HO O OH si 6 O OHC 1 O O 2 re re OHC OHC 16 18 17 R1 R2 T (˚C) t (h) re/si H Bn H Et H Bn 20 40 40 3.5 17 17 60:40 69:31 34:66 endo/exo Yield (%) 100:0 95:5 93:7 90 86 95 Scheme 6.8 C-Disaccharide analogs of trehalose were recently [20c] prepared by using as a key step an aqueous Diels±Alder reaction between the sodium salt of glyoxylic acid and the water soluble homochiral glucopyranosil-1,3-pentadiene 19 (Equation 6.1). A mixture of four diastereoisomers in a 41:24:21:14 proportion was obtained after esterification with methanol and acetylation. The main diastereoisomer 20 was isolated and characterized as benzoyl-derivative. OH O O HOHO + HO (E/Z = 90:10) 19 H CO2Na OAc 1. H2O, 140 ⬚C, O 48 h AcO AcO AcO 2. MeOH/H O 3. Ac2O/Py H CO2Me 6:1 20 Aqueous Diels±Alder reaction has also been applied at the industrial level. 2,2,5-Trisubstituted tetrahydrofurans 21 are a class of active azole antifungals. Workers at Schering-Plough [21] developed a synthetic approach based on a Diels±Alder reaction between 2-arylfurans 22 and ethyl acetylenedicarboxylate (Scheme 6.9). Under thermal conditions the reaction gave a low yield of Diels±Alder Reaction in Unconventional Reaction Media O N 261 Z = NCHMe2,SO2 X, Y = H, F, Cl Z X O N Y N 21 N CO2Et O O CO2Et X O CO2Et CO2Et thermal X X=H Y = Cl CO2Et Y CO2Et Y Cl 23 22 O H2O, 22−45 ⬚C, 24 h, 60−90% X = H Y = Cl X =Y = F X = Y = Cl O CO2Et CO2Et Pt/H X CO2Et Y X CO2Et Y 23 24 Scheme 6.9 a useless product since cycloadduct 23 underwent a retro-Diels±Alder reaction. In water, the desired adducts 23 can be easily isolated in high yield and then be converted into the biologically active compounds 21 via chemoselective hydrogenation and regioselective manipulation of the dihydrofuran moiety of 24. 6.1.2 Catalyzed Diels±Alder Reaction Catalyzed organic reactions in water, and the aqueous Diels±Alder reactions in particular, are currently a topic of great interest [3f±h]. Simple imines are poor dienophiles and must be activated by protonation or by attaching an electron-withdrawing group to the nitrogen atom. Scheme 6.10 illustrates the Diels±Alder reactions of benzyliminium ion 25, generated in situ from an aqueous solution of benzylamine hydrochloride and commercial aqueous formaldehyde, with methylsubstituted 1,3-butadienes [22]. This aqueous Diels±Alder reaction combines three components (an aldehyde, an amine 262 Diels±Alder Reaction in Aqueous Medium salt and a diene) and occurs under mild conditions and with satisfactory yields. The highly reactive cyclopentadiene reacts quantitatively in three hours at 25 8C [22]. R3 R4 BnNH3 Cl + H 2O HCHO R1 R1 R2 R2 [BnNH=CH2]Cl H2O N R3 25 Bn R4 R1 R2 R3 R4 T (˚C) t (h) Yield (%) H H Me Me H H H Me 35 25 70 59 23 45 H Me Me H 35 48 64 Me H H Me 55 96 62 Scheme 6.10 The intramolecular version, achieved by using both dienyl amine and dienylaldehydes, has also been investigated and applied to the synthesis of dihydrocannivonine [23] (Scheme 6.11). The aqueous aza-Diels±Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln OTf3 , triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diastereoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b±d] to the synthesis of azasugars (Scheme 6.14). CHO + MeN MeNH3 Cl H2, Pt/C H2O-EtOH 1:1 70 ⬚C, 30 h, 66% MeN 60% dihydrocannivonine Scheme 6.11 CH NHMe Cl Diels±Alder Reaction in Unconventional Reaction Media 263 R3 R1 R1 BnNH3 Cl H2O + HCHO [BnNH=CH2]Cl 25 R2 R2 H2O, r.t. Ln(OTf)3, 10−12 h R3 N Bn Yield (%) R1 R2 R3 Ln H Me Me Nd 93 23 Me H Me Yb 92 54 catalyzed uncatalyzed Scheme 6.12 H2O BnNH3 Cl + RCHO R [BnNH=CHR]Cl H2O, r.t. Ln(OTf)3, 12−20 h N R + N Bn (exo) Bn (endo) Yield (%) R Ln endo/exo Me(CH2)4 Me(CH2)4 Me(CH2)4 Bn Pr Er Yb Yb 74:26 73:27 72:28 80:20 68 46 62 72 7 4 4 3 Ph Yb 99:1 7 0 catalyzed uncatalyzed Scheme 6.13 H2O, r.t., 48 h N Nd(OTf)3, 44% HO HO Bn O H O H O O N H OH H OH O [BnNH3]Cl + HOH2C O OH HO OH CHO OH H2O, r.t., 60 h Nd(OTf)3 N O OH Bn Scheme 6.14 HO OH HO HO H N H H O OH 264 Diels±Alder Reaction in Aqueous Medium Iminium ions bearing an electron-withdrawing group bonded to the sp2 carbon of the iminium function are very reactive dienophiles. Thus, iminium ions 26 generated from phenylglyoxal (Scheme 6.15, R Ph) or pyruvic aldehyde (R Me) with methylamine hydrochloride, react with cyclopentadiene in water at room temperature with good diastereoselectivity [25] (Scheme 6.15). If glyoxylic acid is used, the formation of iminium salt requires the free amine rather than the amine hydrochloride. O [BnNH=CHCOR]Cl H2O, r.t. + O R N 26 Me (exo) R t (h) exo/endo Yield (%) Ph Me 22 81:19 82 20 78:22 67 R + N Me (endo) Scheme 6.15 Lanthanide triflates catalyze the Diels±Alder reaction of imines, generated from anilines and aldehydes, with both dienes and alkenes [26]. Thus N-benzylideneaniline in the presence of Yb OTf3 (Scheme 6.16) reacts in organic solvent with open-chain dienes, such as Danishefsky's diene, to give tetrahydropyridine derivatives, while with cyclopentadiene and vinylethers and vinylthioethers it works like azadiene in both organic solvent and aqueous medium, affording tetrahydroquinoline derivatives. Ar OSiMe OMe Ar H MeCN, Yb(OTf)3, 0 ⬚C, 92% N C Ph Ph N O H H2O/EtOH/PhH, Yb(OTf)3, 90% Ar = p-Cl-C6H4 Scheme 6.16 H N Ar Ph Diels±Alder Reaction in Unconventional Reaction Media 265 The cycloaddition of glyoxylic acid with cyclopentadiene in water at pH 6 and 60 8C is slow and occurs with low yield and low diastereoselectivity [18] (Scheme 6.17). Proton (pH 0.9) [18], copper salts [27] and Bi OTf3 [28] accelerate the reaction and increase the diastereoselectivity. The lactones 28 and 29 originate from endo and exo cycloadducts 27, respectively. The proposed rearrangement is depicted in Scheme 6.17 for the major endo adduct 30. A competitive ene reaction that originates 28 and 29 cannot be excluded [28]. H O H2 O + H O CO2H CO2H OH H O + O H H 28 29 catalyst t(h) T(8C) 28/29 Yield(%) pH=6 pH=0.9 Cu2 Bi(OTf)3 24 1.5 3 2 60 40 60 40 60:40 73:27 65:35 82:18 16 83 63 86 OH H O O O 27 cat. OH O cat. O O O OH 30 O O H H 28 Scheme 6.17 Engberts [3e, f, 9, 29] investigated the influence of metal ions (Co2 , Ni2 , Cu2 , Zn2 ) on the reaction rate and diastereoselectivity of Diels±Alder reaction of dienophile 31 (Table 6.5, R NO2 ) with cyclopentadiene (32) in water and organic solvents. Relative reaction rates in different media and the catalytic effect of Cu2 are reported in Table 6.5. 10 2 m Cu NO3 2 accelerates the reaction in water by 808 times, and when compared with the uncatalyzed reaction in MeCN by a factor of 232 000. Cu2 is the best catalyst and, for the reaction of 31 (R H) with cyclopentadiene (32), it is 25 times more active than Ni2 and 55 times more active than Co2 or Zn2 . 266 Diels±Alder Reaction in Aqueous Medium Table 6.5 Relative reaction rates of Diels±Alder reaction of 31 (R NO2 ) with 32 in different media and catalytic effecta of Cu2 ion R R O 25 ⬚C R = NO2 + O R + N N O N 32 31 a (endo) Medium krel Catalytic effecta MeCN EtOH H2 O CF3 CH2 OH 10 2 m HCl in H2 O 10 2 m Cu NO3 2 in EtOH 10 2 m Cu NO3 2 in MeCN 10 2 m Cu NO3 2 in H2 O 1 2.7 287 482 5442 58 357 158 000 232 000 19 21 576 158 000 808 (exo) Relative rate between the catalyzed and uncatalyzed reaction in the same solvent. The complex obtained from commercially available chiral a-amino acids (AA) with Cu2 ion induces asymmetry in the Diels±Alder reaction of 31 (R H) with 32. By using 10 % Cu(II)-AA (AA l -abrine) the cycloaddition occurs endo-stereoselectively in 48 h at 0 8C with high yield and with acceptable enantioselectivity (ee 74 %). This is the first example of enantioselective Lewis-acid catalysis of an organic reaction in water [9b]. Indium trichloride [30] and methylrhenium trioxide [31] catalyze the aqueous Diels±Alder reaction of acrolein and acrylates with cyclic and openchain dienes. Some examples of the cycloaddition of methyl vinyl ketone with 1,3-cyclohexadiene are reported in Scheme 6.18. MeReO3 does not give satisfactory yields for acroleins and methyl vinyl ketones with substituents at the b-position and favors the self-Diels±Alder reaction of diene. Diels±Alder Reaction in Unconventional Reaction Media O O H2O + 267 + r.t. O (endo) t (h) catalyst endo /exo (exo) Yield (%) InCl3 4 90:10 87 MeReO3 16 99:1 91 Scheme 6.18 The Diels±Alder reaction can be greatly enhanced by high pressure (Chapter 5) but the effect of pressure is generally weaker in aqueous medium than in organic solvent. Results of high pressure-mediated Diels±Alder reactions of furans and acrylates in water and dichloromethane are reported in Table 6.6 [32]. In aqueous medium the cycloadditions occur with lower yields and less diastereoselectivity than in dichloromethane and, in some cases, addition±substitution reactions were observed. Table 6.6 Diels±Alder reactions of furans with acrylates in water and dichloromethane under high pressure O Y X + 30−33 ⬚C, 24 h O O 3−11 Kbar + X Y X (endo) a b Medium X Y H2 O CH2 Cl2 H2 O CH2 Cl2 H2 O CH2 Cl2 H H H H Me Me COMe COMe CN CN CN CN At 3 kbar. Yield ratio at 3 vs 11 kbar. (exo) endo/exoa Wb 62:38 74:26 67:33 67:33 26:74 31:69 3.9 5.1 4.1 4.6 3.1 5.3 Y 268 Diels±Alder Reaction in Non-Aqueous Polar Systems 6.2 DIELS±ALDER REACTION IN NON-AQUEOUS POLAR SYSTEMS After the discovery of the remarkable acceleration of some Diels±Alder reactions performed in water, a number of polar non-aqueous solvents and their salty solutions were investigated as reaction medium. This revolutionized the concept that the Diels±Alder reaction is quite insensitive to the effect of the medium and emphasized that a careful choice of the solvent is crucial for the success of the reaction. The polarity of the reaction medium is an important variable which also provides some insights into the mechanism of the reaction. If the reaction rate increases by using a polar medium, this means that the transition state probably has polar character, while the absence of a solvent effect is generally related to an uncharged transition state. In the following paragraphs the influence of some representative non-aqueous polar systems on the Diels±Alder reaction is illustrated. 6.2.1 Lithium Perchlorate±Diethyl Ether During 1989±93 lithium perchlorate±diethyl ether (LiClO4 Et2 O, LP-DE) was studied as a reaction medium in organic synthesis when it was observed that cycloadditions, sigmatropic rearrangements, Michael additions and aldol condensations carried out in LP-DE occurred quickly and selectively under mild reaction conditions [33]. In addition, LP-DE allowed the reaction and subsequent work-up to be carried out under essentially neutral conditions. Initially the LP-DE effect was ascribed to the high internal pressure generated by the solubilization of the salt in diethyl ether [34]. Today the acceleration is explained in terms of Lewis-acid catalysis by the lithium cation [35]. The contribution of both factors (internal pressure and lithium cation catalysis) has also been invoked [36]. LP-DE has a weaker catalytic activity than BF3 Et2 O, AlCl3 and TiCl4 because the Lewis acidity of the lithium cation is moderated by complexing with diethyl ether and perchlorate anion [37], but it becomes a highly oxophilic Lewis acid when concentrated solutions are used [38]. The concentration of LP-DE is therefore sometimes essential for the success of the reaction. Grieco and coworkers first observed [34] that 5.0m LP-DE is an extraordinary medium for facilitating Diels±Alder reactions at room temperature. Schemes 6.19 and 6.20 illustrate some examples. Diels±Alder Reaction in Unconventional Reaction Media CO2Et + 269 r.t., 5 h CO2Et 5.0M LP-DE endo/exo = 89:11, yield 93% endo/exo = 80:20, yield 73% H 2O O RO N CO2Et + HN RO OR CO2Me 5.0M LP-DE PhH 60 r.t., 5 h, endo/exo = 75:25, yield 80% ⬚C, 72 h, endo/exo = 8:92, yield 74% O O O + S O r.t. O S O O A 5.0M LP-DE DCM O O S O + O O B 9.5 h, A/B = 85:15, yield 70% 6 h, 15 kbar, A/B = 85:15, yield 100% Scheme 6.19 The reaction of furan with 2,5-dihydrothiophene-3,4-dicarboxylic anhydride is remarkable (Scheme 6.19). Furan is a poor diene and requires high pressure to affect cycloadditions [39]. On the other hand, high temperatures are forbidden because cycloaddition products derived from furan undergo cycloreversion under these conditions. In 5.0m LP-DE, the Diels±Alder reaction of furan with 2,5-dihydrothiophene-3,4-dicarboxylic anhydride proceeds at room temperature and atmospheric pressure in 9.5 h with 70 % yield and with the same diastereoselectivity found when the reaction is carried out under high pressure [40]. The result of the cycloaddition of cyclopentadiene with methylbenzoquinone (Scheme 6.20) is also interesting. In 5.0m LP-DE, diasteroisomeric bis adducts are formed, while in the absence of LP-DE, only one 1:1 adduct is obtained quantitatively. 270 Diels±Alder Reaction in Non-Aqueous Polar Systems O O 5.0M LP-DE O + r.t., 10 h, 74% O O A + B A/B = 6:1 O Et2O 100% O O Scheme 6.20 LP-DE also promotes and accelerates intramolecular Diels±Alder reactions of low reactive polyenones. The use of a catalytic amount of camphorsulfonic acid (CSA) further accelerates the cycloaddition and enhances the diastereoselectivity [41]. Table 6.7 illustrates the effect of CSA on the intramolecular Diels±Alder reaction of 2-methyl-1,7,9-decatrien-3-one. In contrast LP-DE gives disappointing results for intramolecular imino Diels±Alder reactions, even in the presence of CSA. This is due to the fact that weak acids become strong acids in highly polar media such as 5.0m LP-DE and the protonation of diene, with concomitant diene isomerization, competes with cycloaddition [42]. This observation was supported by using trifluoroacetic acid (TFA). The imine 33 (Scheme 6.21) in LP-DE at room temperature in the presence of TFA gave a 1:1 mixture of cycloadduct 34 and the isomerized diene 35 within the unreacted imine 33. No Diels±Alder cycloadduct 36 was detected. Table 6.7 Intramolecular Diels±Alder reaction of 2-methyl-1,7,9-decatrien-3-one O O O + H H A Medium T (8C) t(h) PhH Ph, Me2 AlCl 5.0 m LP-DE 5.0 m LP-DE/CSA (1.0 mol%) 30 mol% LP-DCM 120 25 25 25 25 18 3 24 1.5 72 B A/B 1.6 3.0 3.0 4.5 2.4 Yield (%) 72 74 65 88 9 Diels±Alder Reaction in Unconventional Reaction Media 271 H TFA N + N N H 5.0M LP-DE 53% 33 34 1:1 35 H H 2O N 95 ⬚C, 38 h 55% H TFA N 5.0M LP-DE 50% 37 36 Scheme 6.21 Similarly, in 5.0m LP-DE, preformed TFA-iminium salt 37 gave a 1:1 mixture of 34 and 35. In contrast, heating 37 in water alone gave the cycloadduct 36 in 55 % yield. Similarly, the iminium salt 38 exposed to 5.0m LP-DE afforded only 13 % of tricyclic amine 39, while heating 38 in water gave the Diels±Alder adduct 39 in high yield (Equation 6.2). H2O H 70 ⬚C, 48 h, 80% TFA N N 5.0M LP-DE 38 6:2 H r.t., 66 h, 13% 39 For the aza-Diels±Alder reaction illustrated above, water works better than LP-DE as a reaction medium, providing the cycloadducts in good yield with outstanding stereocontrol. a,b-Unsaturated cycloalkenones are poor dienophiles and do not undergo Diels±Alder reaction in 5.0m LP-DE. The corresponding ketals, on the contrary, give facile cycloaddition in 4.0m LP-DE containing 1.0 mol % of CSA [43] (Scheme 6.22). Analogous results were obtained in 5.0m LP-DE, while the reaction rate was slower in 3.0m LP-DE. When CSA was used in the absence of LP-DE, no reaction occurred. The procedure has been successfully extended to ketals of acyclic a,b-unsaturated ketones, ketals of lactones and orthoesters, and intramolecular cycloaddition of ketals (Scheme 6.22) [43]. 272 Diels±Alder Reaction in Non-Aqueous Polar Systems O O R1 R + 4.0M LP-DE, CSA O R O R1 r.t.-0 ⬚C, 30 min, 71−96% H R, R1 = H, Me O 4.0M LP-DE, CSA O + r.t., 1 h, 80%, endo/exo 93:7 O O O O 5.0M LP-DE, CSA + O r.t., 20 h, 74% O O O H H O O O O 5.0M LP-DE, CSA R H O O R r.t., 21 h, 65−76% R = H, Me O O H 5.0M LP-DE, CSA O O r.t., 1.5 h, 94% H Scheme 6.22 A recent example of the effectiveness of LP-DE on the Diels±Alder reaction is the intramolecular cycloaddition of 2-amidofurans containing a tethered alkenyl group during the synthesis of pyrrolophenanthridine alkaloids [44]. Furanamide 40 (Scheme 6.23) fails to undergo Diels±Alder reactions even at temperatures as high as 240 8C in toluene. The use of 4.0m LP-DE allows the cyclohexanone 41 to be isolated at 100 8C in 24 h in 68 % yield. The reaction involves an initial intramolecular Diels±Alder reaction to give 42, followed by ring opening to give the iminium 43 which then hydrolyzes to 41. Diels±Alder Reaction in Unconventional Reaction Media MeO2C MeO2C COPh N O 273 O LP-DE N COPh 100 ⬚C, 24 h 68% 42 40 Li O MeO2C LiO H2O NHCOPh MeO2C N COPh OH 43 41 Scheme 6.23 6.2.2 Lithium Perchlorate±Nitromethane Lithium perchlorate in nitromethane (LP-NM) is sometimes a more effective reaction medium than LP-DE for certain Diels±Alder reactions. The cycloaddition of 2,3-dimethylbutadiene with nitrostyrenes (Scheme 6.24) occurs with low O2N + NO2 Ar Medium T(8C) t(h) Ar conversion(%) PhMe 5.0M LP-DE 4.0M LP-NM 115 r. t. r. t. 48 24 67 22-54 7-13 83-86 O2N + NO2 NO2 + R* R* OBn O R* = H R* O Me H medium T(8C) PhMe 5.0M LP-DE 4.0M LP-NM 115 r. t. r. t Scheme 6.24 t(h) 24 72 38-96 conversion (%) 54-65 60-88 98-100 274 Diels±Alder Reaction in Non-Aqueous Polar Systems conversion both in toluene under reflux conditions and in 5.0m LP-DE. In 4.0m LP-NM, however, a high conversion is achieved [45]. Analogously, by using a suitable reaction time, the conversion of the Diels±Alder reaction of homochiral a,b-unsaturated nitroalchenes is quantitative in 4.0m LP-NM and the diastereoisomeric excesses are acceptable (Scheme 6.24). The effectiveness of LP-NM with respect to LP-DE has also been proven by the cycloaddition of ketals of a,b-unsaturated ketones with open-chain and cycloaliphatic dienes [46]. In 4.0m LP-NM the Diels±Alder reaction occurs with good yields and selectivities without using CSA, which is absolutely necessary when the reaction is performed in LP-DE (Section 6.2.1). Some examples are illustrated in Scheme 6.25. O O O + 4.0M LP-NM r.t., 65 h, 65% Ph O Ph O O + 4.0M LP-NM r.t., 4.5 h, 70%, endo/exo 93:7 O O Scheme 6.25 The rate enhancement of the Diels±Alder reaction in LP-NM has been attributed to the high dipole moment of nitromethane (3.40 D) in comparison with diethyl ether (1.33 D). 6.2.3 Lithium Trifluoromethanesulfonimide in Acetone or Diethyl Ether A convenient alternative to LP-DE is lithium trifluoromethanesulfonimide (LiNTf 2 ) in acetone or diethyl ether (LT-AC, LT-DE). Representative examples are the Diels±Alder reactions of citraconic anhydride with cyclopentadiene and of dimethyl acetylenedicarboxylate with isoprene [47] (Scheme 6.26). Diels±Alder Reaction in Unconventional Reaction Media 275 O O O + O O O Medium T (˚C) t (h) Yield (%) 4.0M LT-AC r. t. 1 88 5.0M LP-DE r. t. 1 84 CO2Me + MeO2C C C CO2Me CO2Me Medium T (˚C) t (h) Yield (%) 4.0M LT-AC 40 7 96 5.0M LP-DE 25 12 94 Scheme 6.26 Table 6.8 reports the relative reaction rates of Diels±Alder reactions of 2,5dimethylbenzoquinone with trans-piperylene in different lithium salt solutions. The data show that the reaction rate depends on the concentration of LT and that in 4.0m LT-AC and 4.0m LT-DE the rate accelerations are comparable to that exhibited in 5.0m LP-DE and 5.0m LP-AC. Table 6.8 Relative reaction rates of Diels±Alder reactions of 2,6dimethylbenzoquinone with trans-piperylene in LiClO4 (LP) and LiNTf 2 (LT) in acetone (AC) and diethyl ether (DE) Medium t (h) Yield (%) O O Medium 1.0 m LT-AC 2.0 m LT-AC 3.0 m LT-AC 4.0 m LT-AC 0.5 4.0 m LT-DE 6 5.0 m LP-DE 0.5 r.t. + O krel Medium 1 3.8 65.4 1.0 m 2.0 m 3.0 m 4.0 m O LP-AC LP-AC LP-AC LP-AC 84 75 94 H krel Medium krel 1.4 3.4 14.6 80.8 5.0 m 5.0 m 4.0 m 4.0 m 265.4 238.5 207.7 246.2 LP-DE LP-AC LT-AC LT-DE 276 Diels±Alder Reaction in Non-Aqueous Polar Systems Interestingly, the cycloaddition of 2-azadiene 44 with N-methylmaleimide in 2.5m LT-DE gave predominantly exo-adduct in contrast to the thermal cycloaddition that is mainly endo-selective (Scheme 6.27). A similar but not so dramatic increase in exo-selectivity was also observed [47] for the cycloaddition of 44 with N-phenylmaleimide. The reaction is kinetically controlled, but the origin of the high exo-selectivity observed in LT-DE is unclear; the polar medium probably favors the more polar exo transition state. O OR N + N R1 1. Diels −Alder 2. MeOH O O HN RO O OR O H H O H N R1 + HN RO H O O R = TBDMS N R1 44 R1 Medium Me Me Ph Ph PhMe 2.5M LT-DE PhMe 2.5M LT-DE T (˚C) t (h) exo/endo Yield (%) 60 r. t. r. t. r. t. 2 0.5 3 0.1 20:80 80:20 15:85 55:45 76 80 80 96 Scheme 6.27 6.2.4 para-Chlorophenol and Ethylene Glycol Harano and colleagues [48] found that the reactivity of the Diels±Alder reaction of cyclopentadienones with unactivated olefins is enhanced in phenolic solvents. Scheme 6.28 gives some examples of the cycloadditions of 2,5-bis-(methoxycarbonyl)-3,4-diphenylcyclopentadienone 45 with styrene and cyclohexene in p-chlorophenol (PCP). Notice the result of the cycloaddition of cyclohexene which is known to be a very unreactive dienophile: in PCP at 80 8C the reaction works, while no Diels±Alder adduct was obtained in benzene. PCP also favors the decarbonylation of the adduct, generating a new conjugated dienic system, and therefore a subsequent Diels±Alder reaction is possible. Thus, the thermolysis at 170 8C for 10 h of Diels±Alder adduct 47, which comes from the cycloaddition of 45 with 1,5-octadiene 46 (Scheme 6.29), gives the multiple Diels±Alder adduct 49 via decarbonylated adduct 48. In PCP, the reaction occurs at a temperature about 50 8C lower than when performed without solvent, and product 49 is obtained by a one-pot procedure in good yield. Diels±Alder Reaction in Unconventional Reaction Media 277 O O Ph E E Ph E + Ph Ph Ph H Ph E E = CO2Me H H 45 Medium T(8C) t(h) endo/exo krel Yield(%) PhH PCP r. t. r. t. 6 1 92:8 80:20 1 4.5 96 91 O O Ph E E Ph H H Ph Ph E + E E = CO2Me 45 medium T(8C) t(h) endo/exo krel yield(%) PhH PCP 80 80 48 72 Ð 50:50 1 8 very low 88 Scheme 6.28 O O Ph E E Ph E PhH + 80 ⬚C, 89% Ph E Ph 45 46 E = CO2Me 47 170 PCP 64% 120 ⬚C 12 h ⬚C − CO 10 h Ph Ph Ph E E E Ph E 49 48 Scheme 6.29 278 Diels±Alder Reaction in Non-Aqueous Polar Systems Spectroscopic measurements indicate that PCP forms hydrogen bonds with carbonyl oxygen atoms of cyclopentadienone in both the ground and transition states, but the transition state is more effectively stabilized than the ground state, so a rate enhancement is observed. The rates of intermolecular Diels±Alder reactions of hydrophobic dienes and dienophiles are significantly increased when the cycloadditions are performed in pure ethylene glycol (EG) [49a]. Some examples are illustrated in Scheme 6.30. This performance is due to the fact that the EG (i) forms extensive hydrogen bonding, (ii) is able to solubilize hydrophobic dienes and dienophiles, and (iii) forms molecular aggregations with the reactants. Protic solvents such as i-PrOH and t-BuOH favor the diastereoselectivity of the reaction of 3-hydroxy-2-pyrone with acrylates [49b]. Further examples of proton-promoted Diels±Alder reactions are reported in Section 4.8. MeOCO O OCOMe Medium Yield (%) 100 ⬚C 0.5 h + PhH H O O H 140 ⬚C 3h + O R PhH 10 EG 100 OH O PhH EG H O 100 O 100 ⬚C 2h + 0 EG O H OH R O 0 100 O R = (CH2)2SnMe3 Scheme 6.30 6.2.5 Ionic Liquids Ionic compounds are generally crystalline solids which have high melting points because of the high energy of interaction between positive and negative ions (the lattice energy). Some big ions interact weakly and the lattice energy is so Diels±Alder Reaction in Unconventional Reaction Media 279 low that the ionic compounds are liquid at room temperature. These liquids are made up entirely of ions and are known as ionic liquids. According to the complexing ability of their anions, ionic liquids are classified as basic, neutral and acidic [50]. Some examples of neutral ionic liquids are reported in Table 6.9. Room temperature ionic liquids are air stable, non-flammable, nonexplosive, immiscible with many Diels±Alder components and adducts, do not evaporate easily and act as support for the catalyst. They are useful solvents, especially for moisture and oxygen-sensitive reactants and products. In addition they are easy to handle, can be used in a large thermal range (typically 40 8C to 200 8C) and can be recovered and reused. This last point is particularly important when ionic liquids are used for catalytic reactions. The reactions are carried out under biphasic conditions and the products can be isolated by decanting the organic layer. Room temperature ionic liquids have been found to be excellent solvents for a number of reactions [50b] such as the isomerization [51], hydrogenation [52] and Friedel±Crafts reactions [53]. A number of Diels±Alder reactions were recently investigated in these systems. Earle and coworkers [54] have performed Diels±Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except BMIMPF4 , and gave almost quantitative yields after 18±24 h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. The use of Lewis acids (ZnI2 , BF3 Et2 O) in ionic liquids, tested in the cycloaddition of but-3-en-2-one with isoprene, increases both the rate and selectivity of the reaction. The ionic liquid remains catalytically active after the work-up and can be reused. Table 6.9 [BMIM]X Typical neutral ionic liquids X OTf, PF6 , BF4 , ClO4 , lactate X NO3 , PF6 ) [ENIM]X [ENIM]Cl AlCl3 organochloroaluminates [BP] Cl AlCl3 [BMIM] 1-butyl-3-methylimidazolium cation [EMIM] 1-ethyl-3-methylimidazolium cation [BP] N-1-butylpyridinium cation 280 Diels±Alder Reaction in Non-Aqueous Polar Systems Table 6.10 Diels±Alder reactions of cyclopentadiene with dimethyl maleate, ethylacrylate and acrylonitrile in neutral ionic liquids R + R1 R Ionic liquid R R1 [BMIM]OTf [BMIM]OTf [BMIM]OTf [BMIM]BF4 [BMIM]PF6 [BMIM]lactate CO2 Me CO2 Et CN CO2 Et CO2 Et CO2 Et CO2 Me H H H H H R1 T (8C) t(h) endo/exo Yield (%) 20 20 20 15 20 20 18 18 24 24 1 24 81:19 86:4 61:39 83:17 89:11 78:22 98 96 98 99 36 99 Similar results were obtained [55] for the Diels±Alder reaction between cyclopentadiene and methyl acrylate carried out in [EMIM]BF4 at 20 8C for 72 h. In [EMIM]X (X OTf, NO3 , PF6 ) the reaction yields were lower [55]. The best yields and the highest endo/exo selectivity were obtained in EtNH3 NO3 [56]. Chloroaluminate ionic liquids (typically a mixture of a quaternary ammonium salt with aluminum chloride: see Table 6.9) exhibit at room temperature variable Lewis acidity and have been successfully used as solvent/catalyst for Diels±Alder reactions [57]. The composition of chloroaluminate ionic liquids can vary from basic ([EMIM]Cl or [BP]Cl in excess) to acidic (AlCl3 in excess) and this fact can be used to affect the reactivity and selectivity of the reaction. The reaction of cyclopentadiene with methyl acrylate is an example (Scheme 6.31). + CO2Me [M]Cl AlCl3 H r.t., 72 h + CO2Me (endo) [M]Cl AlCl3 (% AlCl3) endo/exo k rel 48 (basic) 84:16 1 51 (acidic) 95:5 24 M = EMIM, BP. Scheme 6.31 Yield (%) 95 79.4 CO2Me H (exo) Diels±Alder Reaction in Unconventional Reaction Media 281 The modest endo/exo ratio observed when the reaction was carried out in basic chloroaluminate ionic liquids is ascribable to the polarity of the medium, while the high diastereoselectivity found in the acidic mixture is due to the increase of Lewis/Bronsted acidity of the medium. The rates of the reactions performed in basic and acidic chloroaluminates (EMIMClAlCl3 , BPClAlCl3 ) are seven times slower and ten times faster, respectively, than those observed when the reactions were carried out in water [57]. 6.3 DIELS±ALDER REACTION IN MICROEMULSION Microemulsions have been known for a century but the chemical research in the field received a great impulse when the price of oil reached levels that made it profitable to recover it by microemulsions. The term microemulsion was first introduced in 1958 and 15 years later the microemulsion was recognized as a special kind of colloidal dispersion [58]. Today microemulsions are used in catalysis, preparation of submicron particles, solar energy conversion, extraction of minerals and protein, detergency and lubrication [58]. Most studies in the field of basic research have dealt with the physical chemistry of the systems themselves and only recently have microemulsions been used as a reaction medium in organic synthesis. The reactions investigated to date include nucleophilic substitution and additions [59], oxidations [59±61], alkylation [62], synthesis of trialkylamines [63], coupling of aryl halides [64], nitration of phenols [65], photoamidation of fluoroolefins [66] and some Diels±Alder reactions. A microemulsion (mE) is a thermodynamically stable, transparent (in the visible) droplet type dispersion of water (W) and oil (O: a saturated or unsaturated hydrocarbon) stabilized by a surfactant (S) and a cosurfactant (CoS: a short amphiphile compound such as an alcohol or an amine) [67]. Sometimes the oil is a water-insoluble organic compound which is also a reactant and the water may contain mineral acids or salts. Because of the small dispersion size, a large amount of surfactant is required to stabilize microemulsions. The droplets Ê [68]), about 100 times smaller than those of a are very small (about 100±1000 A typical emulsion. The existence of `giant' microemulsions (dispersion size about Ê ) has been demonstrated [58]. 6000 A On a microscopic scale, a microemulsion is a heterogeneous system and, depending on the relative amounts of the constituents, three main types of structures can be distinguished [69]: oil in water (O/W, direct micellar structure), water in oil (W/O, reverse micellar structure) and a bicontinuous structure (B) (Figure 6.1). By adding oil in water, O/W dispersion evolves smoothly to a W/O dispersion via bicontinuous phases. Microemulsions are excellent solvents for both non-polar organic molecules and inorganic reagents; they allow high local concentration of reactants and a 282 Diels±Alder Reaction in Microemulsion WATER WATER OIL OIL OIL B O/W S: WATER W/ O CoS: Figure 6.1 large internal interface and permit the reactants to assume preferential orientations. Therefore, a fast reaction rate and high selectivity are expected. Reactions usually take place at the oil±water interface in the micellar phase, but examples of reactions that occur in the bicontinuous phase are also known [70]. Non-aqueous microemulsions have been prepared by replacing water with formamide, a highly structured polar solvent [71]. Formamide enhances the solubility of organic compounds and is also used as a reactant. Physical±chemical studies require traces of additives (reactants, catalysts, electrolytes) with respect to the concentration of the basic components of the microemulsion, and this causes only a minor change in the phase behavior of the system. However, when the amounts of additives are on the scale used in organic synthesis, the phase behavior, which is very sensitive to the concentration of the reactants, is sometimes difficult to control and the reaction is carried out in a one-, two- or three-phase state. The Diels±Alder reaction of methyl methacrylate with cyclopentadiene was studied [72] with solutions from three different regions of the pseudophase diagram for toluene, water and 2-propanol, in the absence and in the presence of surfactant [sodium dodecyl sulfate (SDS) and hexadecyltrimethylammonium bromide (HTAB)]. The composition of the three solutions (Table 6.11) corresponds to a W/O-E (A), a solution of small aggregates (B) and a normal ternary solution (C). The diastereoselectivity was practically constant in the absence and in the presence of surfactant; a slight increase of endo adduct was observed in the C medium in the presence of surfactant. This suggests that the reaction probably occurs in the interphase and that the transition state has a similar environment in all three media. The diastereoselection of the Diels±Alder reaction of methyl acrylate with cyclopentadiene was investigated [74] in microemulsions prepared with isooctane oil, CTAB as surfactant and 1-butanol as cosurfactant, and the results were compared with those found in pure solvents and water (Table 6.12). In emulsions rich in 1-butanol and formamide (entries 1 and 4) the reaction was slow (72 h) and the diastereoselectivity was practically the same as that Diels±Alder Reaction in Unconventional Reaction Media 283 Table 6.11 Diastereoselectivity of Diels±Alder reaction of methyl methacrylate with cyclopentadiene performed in ternary solutions 26 ⬚C, 3 d CO2Me + + CO2Me CO2Me (exo) (endo) Composition (mL %) exo (%) Medium H2 O 2-PrOH PhH Nonea HTAB SDS A B C 4.9 4.9 5.2 44.6 56.9 71.5 50.5 38.2 23.3 63.2 63.4 63.5 63.9 60.9 54.2 63.5 60.5 53.5 a No added surfactant. observed in pure solvents (entries 6 and 7). In the microemulsion mE-3 (reverse micelles), the reaction took place in the continuous phase and the endo/exo ratio was close to that found in pure isooctane. In the formamide-rich microemulsion mE-4 (direct micelles), the diastereoselections were virtually the same as those observed in 1-butanol-rich emulsion mE-1. It would seem that the reaction takes place at the micelle interface in the continuous formamide phase. Table 6.12 Diastereoselectivity of Diels±Alder reaction of methyl acrylate with cyclopentadiene in formamide microemulsion and pure solvents + 20 ⬚C CO2Me + CO2Me CO2Me (endo) (exo) Composition (weight %) Entry Medium 1 2 3 4 5 6 7 8 mE-1 mE-2 mE-3 mE-4 C8 H18 HCONH2 1-BuOH H2 Oe a Isooctane, b Formamide, C8 Ha18 1 92 72 3 100 c 1-Butanol, HCONHb2 6 0.2 4 46 100 d CTABd 1-BuOHc 90 7.7 22 28 3 0.1 2 23 100 Cetyltrimethylammoniumbromide, e only water. Endo (%) 82 74 79 82 70 83 83 9073 284 6.4 Diels±Alder Reaction in Supercritical Fluids DIELS±ALDER REACTION IN SUPERCRITICAL FLUIDS A fluid is described as supercritical or subcritical if its temperature is above or below its critical temperature. Above the critical temperature the liquid and vapor phases are indistinguishable, the densities of the two phases become identical and the substance is described as a fluid, the physical properties of which are intermediate between those of a liquid and a gas [75]. Supercritical fluids (SCFs) have densities similar to those of liquids and a solvent power higher than that of gases, so that compounds which are insoluble in a fluid in ambient conditions become soluble in fluids under supercritical conditions [75]. Critical data for some substances, which are frequently used as solvents under supercritical conditions in chemical reactions, are reported [76] in Table 6.13. Table 6.13 Critical temperature (Tc ), pressure (Pc ), density (Dc ) and molar volume (Vc ) for selected substances substance Tc (8C) Carbon dioxide 30.9 Ethane 32.2 Ethanol 240.7 Ethylene 9.1 Propane 96.6 Water 373.9 Pc (bar) Dc g=cm3 ) Vc cm3 =mol 73.7 48.8 61.4 50.4 42.5 220.6 0.47 0.20 0.28 0.21 0.22 0.32 94 145.5 168 131 200 56 Although SCFs have been known for a long time, they have received attention in organic chemical research and industrial application only during the last two decades [76a, 77]. Today SCFs are used for natural product extractions, chromatographic separations, pollution prevention, material processing and as solvents for chemical reactions.[75±77] Chemical applications include catalysis, polymerization, enzymatic reactions and organic synthesis. The use of SCFs as solvents influences the reacting system because it is possible to dramatically change the density of the fluid with small perturbations of temperature and pressure and, in such a way, greatly affect the densitydependent bulk properties such as the dielectric constant, solubility and diffusibility of these compressible fluids. Carbon dioxide and water are the most commonly used SCFs because they are cheap, nontoxic, nonflammable and environmentally benign. Carbon dioxide has a more accessible critical point (Table 6.13) than water and therefore requires less complex technical apparatus. Water is also a suitable solvent at temperatures below its critical temperature (superheated water). Other fluids used frequently under supercritical conditions are propane, ethane and ethylene. Diels±Alder Reaction in Unconventional Reaction Media 285 A number of Diels±Alder reactions have been investigated in supercritical media and some of them will be illustrated. Most of the research has been focused on the influence of the pressure, which greatly influences the density of the fluid, on the kinetic aspects and on the product distribution of the reaction. 6.4.1 Diels±Alder Reaction in Supercritical Water (sc-H2 O) Water in its supercritical state has fascinating properties as a reaction medium and behaves very differently from water under standard conditions [77f]. The density of sc-H2 O as well as its viscosity, dielectric constant and the solubility of various materials can be changed continuously between gas-like and liquid-like values by varying the pressure over a range of a few bars. At ordinary temperatures this is not possible. For instance, the dielectric constant of water at the critical temperature has a value similar to that of toluene. Under these conditions, apolar compounds such as alkanes may be completely miscible with scH2 O which behaves almost like a non-aqueous fluid. Water reaches supercritical conditions at 373.9 8C (Table 6.13) but it becomes a suitable solvent at 200±350 8C and at pressures generated solely by the expansion of the liquid medium, about 20±100 bar (subcritical or superheated water). Among the reactions studied in supercritical and subcritical water [77f, 78] the first report on a Diels±Alder reaction appeared in 1997 [79]. The results of Diels±Alder reactions of cyclopentadiene with diethyl fumarate, diethyl maleate and ethyl acrylate carried out in sc-H2 O are reported in Scheme 6.32 [79]. The cycloaddition of diethyl fumarate occurred with low yield, H CO2Et sc-H2O + R1 CO2Et R2 H 375 ⬚C R2 R1 R1 Yield (%) 1 − 10 1 2 50:50 50:50 86 80 t (h) CO2Et H H H CO2Et H H R1 CO2Et R2 endo /exo R2 + Scheme 6.32 while the other two dienophiles gave better results. The stereoselectivity of cycloaddition of ethyl acrylate depended on the reaction temperature and reaction time because the reaction undergoes reversion upon heating: at 375 8C after 2 h 50 % endo-adduct was observed, increasing to 75 % after 6 h. Some other Diels±Alder reactions have been investigated in subcritical water [79] and some of them are illustrated in Scheme 6.33. The cycloadditions are fast and occur with good yields. In the absence of solvent, the reagents tend 286 Diels±Alder Reaction in Supercritical Fluids to polymerize upon heating and no reaction occurs in water at temperatures below 280 8C. CO2Et CN CO2Et CO2Et H2O EtO2C CN H2O R1 = Me, R2 = H R1 = R2 = H 303 ⬚C, 0.5 h, 88% 337 ⬚C, 1 h, 84% R1 O R2 CN CN H H2O H2O R1 = R2 = Me 293 ⬚C, 25 min, 100% O O R1 = R2 = Me 310 ⬚C, 0.5 h, 86% H O Scheme 6.33 6.4.2 Diels±Alder Reaction in Supercritical Carbon Dioxide (sc-CO2 ) Above 30.9 8C, CO2 cannot be liquefied by compression; it exists in a supercritical fluid phase (sc-CO2 ) that behaves like a gas that is denser than liquid CO2 . Below 30.9 8C, CO2 can be maintained as a liquid under relatively modest pressure; generally sc-CO2 has better solvent properties than CO2 in the subcritical liquid phase. With sc-CO2 high solubilities can be attained by increasing the pressure, and reactions can be carried out over a wide range of temperatures, pressures and densities. sc-CO2 is readily available, nontoxic, nonflammable, chemically inert under many conditions, inexpensive, environmentally acceptable and easy to remove and recycle. It has received considerable attention as a reaction medium for organic synthesis [77d, 80] as well as in some large-scale extraction processes in food chemistry [81]. The Diels±Alder reaction in sc-CO2 has been investigated quite thoroughly. The diastereoselectivity of the cycloaddition of cyclopentadiene with methyl acrylate in sc-CO2 at 40 8C and subcritical liquid CO2 at 22 8C is practically the same (endo=exo 75:25 and 76:24 respectively) and is comparable to that found in hydrocarbon solvents (73:27 and 75:25 in heptane and cyclohexane, respectively). This shows that CO2 , in these states, behaves like an apolar solvent with very low polarizability [82]. The effect of pressure on the rate constant of the Diels±Alder reaction between maleic anhydride and isoprene was investigated in sc-CO2 at 35 8C and at pressures ranging from 90 to 193 bar. For comparison purposes, the reaction was also carried out in an apolar solvent such as propane under Diels±Alder Reaction in Unconventional Reaction Media 287 subcritical conditions (80 8C and 90±152 bar) [83]. In sc-CO2 , the mole fractionbased rate constants varied linearly with the density of the solution, while in subcritical propane the rate constants deviated from a linear dependence on density at the lower pressures studied. The Diels±Alder reactions of maleic anhydride with 1,3-cyclohexadiene, as well the parallel reaction network in which maleic anhydride competes to react simultaneously with isoprene and 1,3-cyclohexadiene [84], were also investigated in subcritical propane under the above reaction conditions (80 8C and 90± 152 bar). The reaction selectivities of the parallel Diels±Alder reaction network diverged from those of the independent reactions as the reaction pressure decreased. In contrast, the same selectivities were obtained in both parallel and independent reactions carried out in conventional solvents (hexane, ethyl acetate, chloroform) [84]. The rate of the Diels±Alder reaction between p-benzoquinone and cyclopentadiene was measured in sc-CO2 and subcritical CO2 [85]. Relative reaction rates at different pressures are reported in Table 6.14. On going from CO2 in the liquid phase (below 31 8C) to sc-CO2 , the reactivity increased significantly only when the reaction was carried out under high pressure. At 30 8C and 60 bar the reaction was 1.36 times faster than when it was performed in diethyl ether at 30 8C and 1 bar. An example of a hetero-Diels±Alder reaction in sc-CO2 is the cycloaddition of anthracene with 4-phenyl-1,2,4-triazoline-3,5-dione, carried out at 40 8C and at a pressures between 75 and 216 bar [86]. The rate constant increases with decreasing pressure and the highest reactivity was observed at the critical pressure. The value of the rate constant at the critical pressure was higher than that observed in liquid CHCl3 and MeCN at the same temperature. At higher pressures, the rate is slower than that in the polar solvents, which reflects the apolar nature of sc-CO2 as a solvent. A systematic study of the effect of pressure and density on the regiochemical course of the Diels±Alder reactions of methyl acrylate and 2-substituted 1,3-butadienes carried out in sc-CO2 was recently reported [87]. The reactions were compared with those carried out in a conventional medium such as toluene. Some results are illustrated in Table 6.15. Table 6.14 Relative rates of cycloadditions of p-benzoquinone and cyclopentadiene in carbon dioxide T(8C) 25 30 35 35 40 40 40 P(bar) 60 60 120 180 120 180 240 krel kT =k25 C 1 1.32 1.40 1.66 1.74 1.85 1.92 288 Diels±Alder Reaction in Supercritical Fluids Table 6.15 Regioselectivity of Diels±Alder reactions of methyl acrylate with 2-substituted-1,3-butadienes in sc- CO2 and PhMe CO2Me R R CO2Me R + + CO2Me sc-CO2 a R T(8C) P (bar) t (d) Me 50 50 50 50 50 50 t-Bu OSiMe3 a b 49.5 117 87 117 90 117 PhMeb para/meta 4 3 3 1 73:27 70:30 71:29 65:35 traces 85:15 1 T(8C) t (d) para/meta 50 145 50 3 0.01 3 69:31 71:29 69:31 110 0.03 87:13 Yield 3±54%, Yield 48±78%. The regioselectivity under supercritical conditions at different pressures varied little from that found in toluene solution; in particular, no reversal in regioselectivity was found in sc-CO2 near the critical pressure [88]. The combination of Lewis-acid catalysis and sc-CO2 has also been investigated. One of these studies involved the AlCl3 -catalyzed Diels±Alder reaction of isoprene and maleic anhydride in sc-CO2 at 67 8C and at 74.5±78.5 bar [89]. The reaction rate was enhanced with respect to the uncatalyzed reaction and an unconcerted two-step mechanism was suggested [89]. A recent report [90] investigated the Diels±Alder reaction of cyclopentadiene with various acrylates in sc-CO2 catalyzed by Sc OTf3 . The results relative to nbutyl acrylate, in sc-CO2 and in conventional solvents, are reported in Scheme 6.34. The catalyzed reaction carried out under supercritical conditions went to completion within 15 h at 50 8C, whereas the uncatalyzed reaction proceeded only to 10 % after 24 h. An increase of endo/exo diastereoselectivity was also observed. O + On-Bu Sc(OTf)3 + 50 ⬚C, 80 bar 15 h, 80% CO2n-Bu Medium P (bar) endo/exo 91:9 PhMe 1 CHCl3 1 92:8 sc-CO2 80 96:4 Scheme 6.34 CO2n-Bu Diels±Alder Reaction in Unconventional Reaction Media 289 Chapuis, Jurczak and coworkers [91] were the first to report the influence of sc-CO2 on the enantioselectivity of a Diels±Alder reaction (Scheme 6.35). At subcritical conditions the conversion of the reaction was poor. The best enantioselectivity was achieved around the critical point and no improvement was observed at higher pressure and temperature. O O + R* sc-CO2 R* O + *R O *R (-) (2R, 3R) N R* = S O (2S, 3S) T(8C) P(bar) Conv.(%)a de(%) 33 43 63 74 78 90 65 100 100 93 92 82 a O R* O *R O Conversion reaction Scheme 6.35 6.5 OUTLINED DIELS±ALDER REACTIONS Reaction of (E)-2,4-pentadienyl ammonium chloride and related ammonium salts with dienophiles in water [92] N O R1 + NH3 Cl n R2 O R1 = Me, OMe R2 = H, Me; n = 1, 2 H2O, 25 ⬚C 2−120 h, 77−99% n R1 R2 O H 290 Outlined Diels±Alder Reactions Aza-Diels±Alder reactions in aqueous solutions: cycloaddition of dienes with simple iminium salts generated under Mannich conditions [22] H2O, 50 ⬚C Cl NH3 + HCHO NH 48 h, 65% Cl H H2O, 70 ⬚C CHO + BnNH3 Cl 20 h, 63% H H + N H Cl Bn H 71% N H Cl Bn 29% Aqueous intermolecular Diels±Alder chemistry: vernolepin revisited [16e] OHC OBn H2O, 50 + ⬚C OHC OBn OBn 1. NaBH4 19 h, 91% COONa 2. H H COONa O O H Immonium ion based synthetic methodology: a novel method for the N-methylation of dipeptides and amino acid derivatives via retro aza-Diels±Alder reactions [93] CH2i-Pr H N H3N Cl O O OMe + HCHO + CH2Ph H2O, r. t. 87% N CH2i-Pr H N O O TFA/Et3SiH OMe CH2Ph endo /exo = 1:1 78% 20 h r.t. N-Me(L)-leucine-(L)phenylalanine Diels±Alder Reaction in Unconventional Reaction Media 291 Intramolecular Diels±Alder cycloadditions of bis-diene substrates [94] 1 CO2R 13 12 13 12 1 11 10 9 RO2C H 2 11 3 9 3 RO2C 4 4 7 H 7 4 13 8 7 3 5 + 5 5 1 6 8 10 8 2 H 10 6 9 H 12 11 6 2 A R=H H2O 100 ⬚C A = 11% B = 89% R = Et H2O 100 ⬚C A = 40% B = 60% ⬚C A = 75% B = 25% R = Et PhMe 165 B Double asymmetric synthesis and a new strategy for stereochemical control in organic synthesis [95] O + O O RO2C RO2C O N O + N N RO2C CO2R N N N CO2R O A R = Bn H2O/EtOH -10 ⬚C R = Bn PhMe 0 ⬚C A/B = 96:4 CO2R B Yield 100% A/B = 93.5:6.5 Yield 100% The oxidation of norbornadiene and some derivatives using Pseudomonas sp [96]. N Ph O O + Ph O H2O N 66% O O O three dienophiles Quinolizidine synthesis via intramolecular immonium ion based Diels±Alder reactions: total synthesis of ()-lupinine, ()-epilupinine, ()-criptopleurine and ()-julandine [97] MeO MeO MeO MeO H 3N Cl MeO + HCHO 50% EtOH-H2O H N 110 ⬚C, 23 h MeO 292 Outlined Diels±Alder Reactions High exoselectivity in Diels±Alder addition of a-vinylidene and a-methylene-g-butyrolactones to cyclopentadiene [98] O O O CH2 C H2O + O O r.t., 99% CH2 O CH2 (endo) (exo) exo /endo = 79:21 Enhanced stereoselectivity in aqueous intramolecular hetero-Diels±Alder cycloaddition of chiral acylnitroso compounds [17c, d, 99] NH H H Bu4NIO4, H2O O OMOM OMOM OMOM 0 ⬚C, 1min, 83% O + N O O OH Et Et Et B A 7 examples A/B = 5:1 N O Aqueous cycloaddition using glyco-organic substrates. Facial stereoselectivity in Diels±Alder reactions of a chiral diene derived from D-glyceraldehyde [102] + H OH CHO H2O 20 ⬚C, 24 h 82% CHO CHO H CH2OH H CH2OH OH CH2OH 65% 35% OH H H H HO OH OH H O O OH Diels±Alder Reaction in Unconventional Reaction Media 293 Asymmetric base-catalyzed Diels±Alder reaction of 3-hydroxy-2-pyrone with chiral acrylate derivatives [106] O O N + O O O i-PrOH-H2O O OH O HO O 0 ⬚C, 100% de = 95% O N O Bronsted acid catalyzed aza-Diels±Alder reaction of Danishefsky's diene with aldimine generated in situ from aldehyde and amine in aqueous media [107] RCHO R H2O-MeOH + ArNH + MeO 2 OSMT ⬚C HBF4, − 40 0.5 h, 58−95% R = Ph, p-MeC6H4, p-NO2C6H4, c-C6H11, BnCH2, i-Pr, 2-Furyl Ar O N Ar, = Ph, p-MeOC6H4 Lanthanide triflates as unique Lewis acids [24d] Ph R Ph + CH2O H2O, Nd(OTf)3 + R1 H2N CO2Me R N r.t., 12−20 h, 96−98% CO2Me R1 Indium trichloride (InCl3 ) catalyzed Diels±Alder reaction in water [30] O R + ( )n H2O, InCl3 ( )n r.t., 4 h, 86−99% COR R = H, Me, OMe n = 1, 2 13 examples Scandium trifluoromethansulfonate (Sc OTf3 ). A novel reusable catalyst in the Diels± Alder reaction [108] O THF-H2O + O Sc(OTf)3, r.t., 93% O O 100% 294 Outlined Diels±Alder Reactions Enhancement of dienophilic and enophilic reactivity of the glyoxylic acid by bismuth (III) triflate in the presence of water [28] R1 R1 R1 H2O, Bi(OTf)3 O R2 + H R2 COOH O r.t.,−100 ⬚C, 2.5−18 h 8-85% O + COOH HO O A R1, R2 = H, Me B A (cis/trans) = 40−64%:60−36% A/B = 43−99%: 57−1% IMIDAF cycloaddition as a method for the preparation of pyrrolophenanthridine alkaloids [44] MeO2C MeO2C O MeO2C O 5M LiClO4/Et2O N N 100⬚C, 36 h, 80% O O O Br N O O O Br O O O Br Dramatic rate accelerations of Diels±Alder reactions in 5m lithium perchlorate±diethyl ether: the cantaridin problem reexamined [34] TBDMSO R 5.0M LiClO4/Et2O + N r.t., 3−5 h, 80% O HN TBDMSO R = CO2Me endo/exo = 75:25 R R = CN endo/exo = 23:77 OSMDBT 8 examples Acid catalyzed intramolecular Diels±Alder reactions in lithium perchlorate±diethyl ether: acid promoted migration of terminal dienes prior to [4 2] cycloaddition in conformationally restricted substrates [101] H 5.0M LiClO4/Et2O O 3 examples H H r.t., 4 h, 10 mol% CSA, 64% O H O Diels±Alder Reaction in Unconventional Reaction Media 295 Acid catalyzed ionic Diels±Alder reactions in concentrated solutions of lithium perchlorate in diethyl ether [43] R1 R2 R4 + O R1 O 4.0M LiClO4/Et2O R2 R4 O O CSA, r.t., 1 h, 71−90% R3 R3 R5 R5 R1-R5 = H, Me The cause of the rate acceleration by diethyl ether solutions of lithium perchlorate in organic reactions. Application to high pressure synthesis [35c] O O H 1.0M LiClO4/Et2O + 300 MPa, 20 ⬚C 5 h, 69% O 5 examples O H Lithium catalyzed hetero-Diels±Alder reactions. Cyclocondensation of N-protected aamino aldehydes with 1-methoxy-3-tert-butyldimethylsilyloxybutadiene in the presence of lithium perchlorate [104] OMe CHO 0.5M LiClO4/Et2O HCl/THF OSMDBT r.t., 11 h, 74% + HNBoc H O H HNBoc O 7 examples Diels±Alder reactions of quinones generated in situ by electrochemical oxidation in lithium perchlorate±nitromethane [105] OH OH R3 HO + CO2Et R2 R1 R1, R2, R3 = H, Me O anodic oxidation LiClO4-MeNO2 r.t., 16 h, 92−98% R3 EtO2C R2 R1 15 examples Catalysis by lithium perchlorate in dichloromethane: Diels±Alder reactions and 1,3Claisen rearrangements [100] + CO2Me LiClO4 (4 mol%) DCM, 22 ⬚C 16 h, 97% + CO2Me 82% CO2Me 18% 296 Outlined Diels±Alder Reactions Can a chiral catalyst containing the same ligand/metal components promote the formation of both enantiomers enantioselectively? The bis(oxazoline)magnesium perchlorate-catalyzed asymmetric Diels±Alder reaction [103] O N O O + N (R) Ph O N O Ph O (R) Mg(ClO4)2, DCM/H2O −80 ⬚C, 48 h, ee 73% endo/exo = 95:5 N O O Lithium trifluoromethanesulfonimide in acetone or diethyl ether as a safe alternative to lithium perchlorate in diethyl ether for effecting Diels±Alder reactions. Unexpected influence of the counterion on exo/endo selectivity [47] MeO MeO CHO + O H CHO 14 4.0M LiNTf2/Me2CO 40 ⬚C, 22 h, 80% H O H COOH COOH C(14)b-H/C(14)a-H = 3.6 7 examples Molecular aggregation and its applicability to synthesis. The Diels±Alder reaction [49] O O ethylene glycol + 150 ⬚C, 6 h, 100% H HO HO Ph Ph 7 examples A safe recyclable alternative to lithium perchlorate±diethyl ether mixture [54] COR CO2Me MeO2C R O R = OEt, Me CO2Me [BMIM]PF6 80 ⬚C, 2 h, 98% [BMIM]BF4 BF3 OEt2 (ZnI2) 20 ⬚C, 2−6 h 90−98% CO2Me Diels±Alder reactions using supercritical water as an aqueous solvent medium [79] R1 R1 CN R2 + R3 R2 303-373 ⬚C 0.5−2 h, 88−100% R4 R1, R4 = H, Ph R2, R3 = H, Me CN R3 R4 12 examples Diels±Alder Reaction in Unconventional Reaction Media 297 REFERENCES 1. Reichhardt C. Solvents and Solvent Effects in Organic Chemistry, 2nd edn, VCH, Weinheim, 1990. 2. (a) Rideout D. C. and Breslow R. J. Am. Chem. Soc. 1980, 102, 7816; (b) Breslow R., Maitra V. and Rideout D. C. Tetrahedron Lett. 1983, 24, 1901; (c) Samii A. A. Z., de Savignac A., Rico I. and Lattes A. Tetrahedron 1985, 41, 3683. 3. (a) Li C. J. and Chang T. H. Organic Reactions in Aqueous Media, Wiley, New York, 1997; (b) Grieco P. A. 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Tetrahedron Lett. 1999, 40, 7831. 108. Kobayashi S., Hachiya I., Araki M. and Ishitani H. Tetrahedron Lett. 1993, 34, 3755. The Diels±Alder Reaction: Selected Practical Methods Edited by Francesco Fringuelli and Aldo Taticchi Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-80343-X (Hardback); 0-470-84581-3 (Electronic) 7 Diels±Alder Reaction Compilation The titles of books, reviews, monographs and symposia proceedings published in the years 1990±2000, together with some edited in the first months of 2001, that were entirely or partly devoted to Diels±Alder reactions, are reported below. Some key words illustrating the subject are included. Sources are given as a four-figure number, the first two figures indicating the year of publication and the second two the sequence; thus 0003 refers to source number 3 of the year 2000, and 9118 to source number 18 of 1991. The numbers are used for reference in a keyword index at the end of the chapter. Unless otherwise specified, the sources are written in English. 7.1 COMPILATION 2001 (0101) Fringuelli F., Piermatti O., Pizzo F., Vaccaro L. Recent Advances in Lewis-Acid Catalyzed Diels±Alder Reactions in Aqueous Media Eur. J. Org. Chem. 2001 439±455 Keywords: water, Lewis acids, carbo-Diels±Alder reactions, hetero-Diels±Alder reactions (0102) Kumar A. Salt Effects on Diels±Alder Reaction Kinetics Chem. Rev. 2001 101 1±19 2000 (0001) Warmuth R The Inner Phase of Molecular Container Compounds As a Novel Reaction Environment J. Inclusion Phenom. Macrocyclic Chem. 2000 37 1±38 Keywords: inclusion reaction, photochemistry, photoinduced electron transfer, fullerenes (0002) Hamers R. J., Coulter S. K., Ellison M. D., Hovis J. S., Padowitz D. F., Schwartz M. P., Greenlief C. M., Russell J. N. Jr Cycloaddition Chemistry of Organic Molecules With Semiconductor Surfaces Acc. Chem. Res. 2000 33 617±624 Keywords: carbonyl group, semiconductor materials, surface reaction, alkenes, aromatic compounds, azo compounds, cycloalkadienes, isothiocyanates, unsaturated compounds (0003) Tokoroyama T. Synthesis of Clerodane Diterpenoids and Related Compounds ± Stereoselective Construction of the Decalin Skeleton With Multiple Contiguous Stereogenic Centers Synthesis 2000 611±633 Keywords: diterpenes, stereoselective construction of the decalin skeleton of clerodane diterpenoids 302 Compilation (0004) Brimble M. A., Nairn M. R., Prabaharan H. Synthetic Strategies Towards Pyranonaphthoquinone Antibiotics Tetrahedron 2000 56 1937±1992 Keywords: biomolecules, pyranonaphthoquinone antibiotics (0005) Nikalje M. D., Phukan P., Sudalai A Recent Advances in Clay-Catalyzed Organic Transformations Org. Prep. Proced. Int. 2000 32 1±40 Keywords: clay catalyzed reactions, montmorillonite catalyst, kaolinite catalyst (0006) Bouaziz Z., Nebois P., Poumaroux A., Fillion H. Carbazole-1,4-Diones: Syntheses and Properties Heterocycles 2000 52 977±1000 Keywords: azadienes, carbazolediones (0007) Mehta G., Uma R. Stereoelectronic Control in Diels±Alder Reaction of Dissymmetric 1,3-Dienes Acc. Chem. Res. 2000 33 278±286 Keywords: stereoelectronic effects, steric effects, alkadienes, cycloalkadienes (0008) Johnson J. S., Evans D. A. Chiral Bis(Oxazoline) Copper(II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions Acc. Chem. Res. 2000 33 325±335 Keywords: hetero-Diels±Alder reaction, chiral bis(oxazoline) copper(II) complexes (0009) Abbenhuis H. C. L. Advances in Homogeneous and Heterogeneous Catalysis With Metal-Containing Silsesquioxanes Chem. Eur. J. 2000 6 25±32 Keywords: Diels±Alder reactions of enones (0010) Rappoport Z. The Chemistry of Dienes and Polyenes vol 2 2000, Wiley, Chichester, N.Y. (0011) Bernath G., Stajer G., Fulop F., Sohar P. A Retro Diels±Alder Synthetic Method. Fused-Skeleton Isoindolones and Further Saturated Hetero Polycycles J. Heterocycl. Chem. 2000 37 439±449 (0012) Carmona D., Pilar Lamata M., Oro, L. A. Recent Advances in Homogeneous Enantioselective Diels±Alder Reactions Catalyzed by Chiral Transition-Metal Complexes Coord. Chem. Rev. 2000 200±202 717±772 (0013) Behforouz M., Ahmadian M. Diels±Alder Reactions of 1-Azadienes Tetrahedron 2000 56 5259±5288 (0014) Wang D., Guo B. Diels±Alder New Reactions Baoji Wenli Xueyuan Xuebao, Ziran Kexueban 2000 20 271±275 (0015) Otto S., Engberts J. B. F. N. Diels±Alder Reactions in Water Pure Appl. Chem. 2000 72 1365±1372 (0016) Wittkopp A., Schreiner P. R. Catalysis of Diels±Alder reactions in water and in hydrogen-bonding environments [Chem. Dienes Polyenes Conference Proceeding] 2000 (0017) Jorgensen K. A. Catalytic Asymmetric Hetero-Diels±Alder Reactions of Carbonyl Compounds and Imines Angew. Chem. Int. Ed. Engl. 2000 39 3558±3588. Keywords: mechanism, enantioselectivity (0018) Klarner F. G., Wurche F. The Effect of Pressure on Organic Reactions J. Prakt. Chem. 2000 342 609±636 (0019) Chauhan K. K., Frost C. G. Advances in Indium-Catalysed Organic Synthesis J. Chem. Soc. Perkin Trans. 1 2000 3015±3019 Keywords: catalyzed organic synthesis Diels±Alder Reaction Compilation 303 (0020) Kobayashi O. Organic Reactions Using Water As Solvent Konbatekku 2000 28 2±6 (0021) Abellan T., Chinchilla R., Galindo N., Guillena G., Najera C., Sansano J. M. Glycine and Alanine Imines As Templates for Asymmetric Synthesis of a-Amino Acids Eur. J. Org. Chem. 2000 2689±2697 Keywords: Diels±Alder cycloaddition, asymmetric synthesis (0022) Tome A. C., Lacerda P. S. S., Silva A. M. G., Neves M. G. P. M., Cavaleiro J. A. S. Synthesis of New Tetrapyrrolic Derivatives-Porphyrins As Dienophiles or Dipolarophiles J. Porphyrins Phthalocyanines 2000 4 532±537 Keywords: Diels±Alder reaction (0023) van Leeuwen P. W. N. M., Kamer P. C. J., Reek J. N. H., Dierkes P. Ligand Bite Angle Effects in Metal-Catalyzed C±C Bond Formation Chem. Rev. 2000, 100, 2741±2769. Keywords: carbon±carbon bond formation (0024) Tietze L. F., Modi A. Multicomponent Domino Reactions for the Synthesis of Biologically Active Natural Products and Drugs Med. Res. Rev. 2000 20 304±322 Keywords: Diels±Alder reactions (0025) Khan F. A., Prabhudas B., Dash J. 1,2,3,4-Tetrachloro-5,5-DimethoxyCyclopenta-1,3-Diene: Diels±Alder Reactions and Applications of the Products Formed J. Prakt. Chem. 2000 342 512±517 Keywords: norbornene derivatives, tetrachlorodimethoxy cyclopentadiene (0026) Vaultier M., Lorvelec G., Plunian B., Paulus O., Bouju P., Mortier J. Recent Developments in the Use of a,b-Unsaturated Boronates As Partners in Diels±Alder Cycloadditions Spec. Publ. ± R. Soc. Chem. 2000 253 464±471 Keywords: diene boryl Diels±Alder cycloaddition (0027) Kitazume T. Organic Synthesis in Ionic Liquids Kagaku Kogyo 2000 51 437±444 (0028) Garcia J. I, Mayoral J. A, Salvatella L. Do Secondary Orbital Interactions Really Exist? Acc. Chem. Res. 2000 33 658±664 (0029) Babu G., Perumal P. T. Synthetic Applications of Indium Trichloride Catalyzed Reactions Aldrichimica Acta 2000 33 16±22 (0030) De Mijere A., Kozhushkov S. I., Khlebnikov AF Bicyclopropylidene ± a Unique Tetrasubstituted Alkene and a Versatile C6±Building Block Top. Curr. Chem. 2000 207 89±147 Keywords: Diels±Alder bicyclopropylidene building block (0031) Zamojski A. Chiral (E,E)-1,4-Dialkoxy-1,3-Butadienes. Synthesis, Conformational Studies and Diels±Alder Reactions with Symmetric Dienophiles Chemtracts 2000 13 62±65 (0032) Saito N., Grieco P. A. Development of Cationic Diels±Alder Reaction in Highly Polar Media and Total Syntheses of Natural Products Yuki Gosei Kagaku Kyokaishi 2000 58 39±49 Keywords: lithium perchlorate diethyl ether 1999 (9901) Jorgensen K. A. Development and application of catalytic highly enantioselective hetero-Diels±Alder reactions of aldehydes and ketones in Curr. Trends Org. Synth., 304 Compilation [Proc. Int. Conf. ], 12th. 1999 207±212, Eds. Scolastico C, Nicotra F, Pb. Acad. Plenum Pub. N.Y. Keywords: aldehydes, ketones, enantioselective hetero-Diels±Alder reactions (9902) Kobayashi S. Catalytic enantioselective reactions of aldimines using chiral Lewis acids in Curr. Trends Org. Synth., [Proc. Int. Conf. ], 12th. 1999 183±190, Eds. Scolastico C., Nicotra F., Pb. Acad. Plenum Pub. N.Y. Keywords: aza-Diels±Alder reactions, imines, aldimines, chiral Lewis acids, asymmetric synthesis (9903) Evans D. A., Rovis T., Johnson J. S. Chiral Copper(II) Complexes As Lewis Acids for Catalyzed Cycloaddition, Carbonyl Addition, and Conjugate Addition Reactions. Pure Appl. Chem 1999 71 1407±1415 Keywords: bis(oxazoline) copper complexes, Lewis-acid catalysts for carbocyclic and hetero-Diels±Alder reaction, chiral synthesis (9904) Goyau B. Fine Chemistry and Acrolein Chim. Oggi 1999 17 22±27 Keywords: acrolein chemistry (9905) Shibasaki M. Multifunctional Asymmetric Catalysis Enantiomer 1999 4 513±527 Keywords: hetero-bimetallic complexes (9906) Stevenson P. J. Synthetic Methods. Part (II). Pericyclic Methods Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 1999 95 19±38 Keywords: pericyclic reaction in organic synthesis (9907) Minuti L., Taticchi A., Costantini L. High Pressure Diels±Alder Reactions of Cycloalkenones in Organic Synthesis Recent Res. Dev. Org. Chem. 1999 3 105±116 Keywords: ketones, regiochemistry, stereoselectivity, reactivity (9908) Shibasaki M. Multifunctional Asymmetric Catalysis Chemtracts 1999 12 979±998 Keywords: hetero-bimetallic complexes (9909) Ooi T., Maruoka, K. Hetero-Diels±Alder and related reactions in Compr. Asymmetric Catal. I-III 1999 3 1237 Eds. Jacobsen EN, Pfaltz A and Yamamoto H, Pb. Springer-Verlarg, Berlin Keywords: catalytic asymmetric hetero-Diels±Alder reaction (9910) Evans D. A., Johnson J. S. Diels±Alder reactions in Compr. Asymmetric Catal. IIII 1999 3 1177 Eds. Jacobsen E. N., Pfaltz A. and Yamamoto H., Pb. SpringerVerlarg, Berlin Keywords: Lewis acids, asymmetric Diels±Alder reactions catalyzed by chiral Lewis-acid complexes (9911) Keay B. A., Hunt I. R. Aspects of the Intramolecular Diels±Alder Reaction of Furan Dienes Leading to the Formation of Epoxydecalin Systems Adv. Cycloaddit. 1999 6 173±210 Keywords: alkadienes, intramol Diels±Alder reaction, furan dienes, epoxydecalin systems (9912) Lee L., Snyder J. K. Indole As a Dienophile in Inverse Electron Demand Diels± Alder and Related Reactions Adv. Cycloaddit. 1999 6 119±171 Keywords: indole as dienophile (9913) Ruano J. L. G., De la Plata B. C. Asymmetric [42] Cycloadditions Mediated by Sulfoxides Top. Curr. Chem. 1999 204 1±126 Diels±Alder Reaction Compilation 305 Keywords: sulfoxides, hetero-Diels±Alder reaction, stereoselectivity, sulfoxide mediator (9914) Nakayama J., Sugihara Y. Chemistry of Thiophene 1,1-Dioxides Top. Curr. Chem. 1999 205 131±195 (9915) Olivier H. Recent Developments in the Use of Non-Aqueous Ionic Liquids for TwoPhase Catalysis J. Mol. Catal. A: Chem. 1999 146 285±289 Keywords: good solvents for Diels±Alder reactions, ionic liquids (9916) Coxon J. M., Froese R. D. J., Ganguly B., Marchand A. P., Morokuma K On the Origins of Diastereofacial Selectivity in Diels±Alder Cycloadditions Synlett 1999 1681±1703 Keywords: p-facial selectivity, MO calculations (9917) Cairns J., Dunne C., Franczyk T. S., Hamilton R., Hardacre C., Stern M. K., Treacy A, Walker BJ The Synthesis and Chemistry of Formylphosphonate Phosphorus, Sulfur Silicon Relat. Elem. 1999 144±146 385±388 Keywords: imines derived from formylphosphonate undergo Diels±Alder reactions only in those cases which carry a strongly electron-withdrawing Nsubstituent. Lewis acidity, solvent effect, lithium perchlorate in diethyl ether (9918) Tarasow T. M., Eaton B. E. The Diels±Alder Reaction and Biopolymer Catalysis Cell. Mol. Life Sci. 1999 55 1463±1472 Keywords: biopolymer, Lewis acids, Diels±Alderase (9919) Nomura T. The Chemistry and Biosynthesis of Isoprenylated Flavonoids From Moraceous Plants Pure Appl. Chem. 1999 71 1115±1118 Keywords: enzymic Diels±Alder reaction (9920) Kobayashi S. Lanthanide Triflate-Catalyzed Carbon±Carbon Bond-Forming Reactions in Organic Synthesis Top. Organomet. Chem. 1999 2 63±118 Keywords: lanthanide triflates, rare earth compounds (9921) Rimmer S., Tattersall P., Ebdon J. R., Fullwood N. New Strategies for the Synthesis of Amphiphilic Networks React. Funct. Polym. 1999 41 177±184 Keywords: Diels±Alder reaction of poly(ethylene glycol) that contain acetylene dicarboxylate groups along the main chain with furan-ended oligomers, amphiphilic gels (9922) Pu L. Rigid and Sterically Regular Chiral 1,10 -Binaphthyl Polymers in Asymmetric Catalysis Chem. ±Eur. J. 1999 5 2227±2232. Keywords: hetero-Diels±Alder reaction of ethylglyoxylate with conjugated dienes (9923) Barluenga J., Suarez-Sobrino A., Lopez L. A. Chiral Heterosubstituted 1,3-Butadienes: Synthesis and [4 2] Cycloaddition Reactions Aldrichimica Acta 1999 32 4±15 Keywords: alkadienes, stereoselectivity, chiral heterosubstituted butadienes (9924) Nishiyama H., Motoyama Y. Other Transition Metal Reagents: Chiral Transition-Metal Lewis Acid Catalysis for Asymmetric Organic Synthesis in Lewis Acid Reagents 1999 225, Ed Yamamoto H., Pb. Oxford Univ. Press, Oxford Keywords: asymmetric Diels±Alder reactions, chiral transition metal Lewis-acid catalysis, asymmetric synthesis (9925) Lorsbach B. A., Kurth M. J. Carbon±Carbon Bond Forming Solid-Phase Reactions Chem. Rev. (Washington, D. C.) 1999 99 1549±1581 Keywords: solid phase synthesis, Diels±Alder reaction 306 Compilation (9926) Fallis A. G. 1998 Alfred Bader Award Lecture. Tangents and Targets: the Synthetic Highway From Natural Products to Medicine Can. J. Chem. 1999 77 159±177 Keywords: intramolecular Diels±Alder reaction, tether-controlled, synthetic studies direct toward various classes of natural products, alkadienes (9927) Shibasaki M., Sasai H. Asymmetric Catalysis With Chiral Lanthanoid Complexes Top. Stereochem. 1999 22 201±225 Keywords: chiral lanthanoid complexes, rare earth complexes, carbocyclic ring construction via intramolecular Diels±Alder reaction (9928) Woodard B. T., Posner G. H. Recent Advances in Diels±Alder Cycloadditions of 2-Pyrones Adv. Cycloaddit. 1999 5 47±83 Keywords: lactones, stereoselective synthesis (9929) Wender P. A., Love J. A. The Synthesis of Seven-Membered Rings: General Strategies and the Design and Development of a New Class of Cycloaddition Reactions Adv. Cycloaddit. 1999 5 1±45 Keywords: seven-membered rings (9930) Klunder A. J. H., Zhu J., Zwanenburg B. The Concept of Transient Chirality in the Stereoselective Synthesis of Functionalized Cycloalkenes Applying the RetroDiels±Alder Methodology Chem. Rev. (Washington, D. C.) 1999 99 1163±1190 Keywords: stereochemistry, stereoselective synthesis, retro-Diels±Alder methodology (9931) Nebois P., Fillion H. Diels±Alder Reactions of Benzo[b]Furan-4,5-Diones and Benzo[b]Furan-4,7-Diones Heterocycles 1999 50 1137±1156 Keywords: benzofurandiones, regiochemistry, heterocyclic compounds (9932) Vaccari A. Clays and Catalysis: a Promising Future Appl. Clay Sci. 1999 14 161±198 Keywords: cationic and anionic clays, catalysis (9933) Fallis A. G. Harvesting Diels and Alder's Garden: Synthetic Investigations of Intramolecular [4 2] Cycloadditions Acc. Chem. Res. 1999 32 464±474 Keywords: intramolecular Diels±Alder reaction (9934) Nesi R., Giorni D. and Turchi S. Synthesis of Nitrogen Heterocycles by Hetero Diels±Alder Reactions in Seminars in Organic Synthesis. 24th Summer Sch ``A. Corbella'' 1999 225, Ed. Trombini, Pb. Soc. Chim. Ital. Keywords: imine, iminium cations, nitriles, nitroso compounds, azo compounds, azadienes, nitroso alkenes (9935) Avenoza A., Busto J. H., Cativiela C., Peregrina G. M. and Zurbano M. M. The use of 4-Hetaryliden- and 4-Aryliden-5(4H)-Oxazolones as Dienophiles in the Diels±Alder Reactions in Targets in Heterocyclic Systems-Chemistry and Properties vol 3. 1999, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. Keywords: hetero-Diels±Alder reactions (9936) Okamura H., Iwagawa M. and Nakatani M. Development of Base Catalyzed Diels±Alder Reaction of 3-Hydroxy-2-Pyrone and Application to Synthesis of Biologically Active Compounds Org. Chem. Japan 1999 57 84 Keywords: hetero-Diels±Alder reactions (9937) Fleming I. Pericyclic Reactions Oxford Science Publications 1999, Pb. Oxford Univ. Press N.Y. Keywords: MO theory, stereoselectivity, regiochemistry, mechanism Diels±Alder Reaction Compilation 307 1998 (9801) Fraile J. M., Garcia J. I., Mayoral J. A. Heterogeneous Catalysis of Diels±Alder Reactions Recent Res. Dev. Synth. Org. Chem. 1998 1 77±92 Keywords: heterogeneous catalysts (9802) Bloch R., Mandville G. Novel Strategies for the Use of Retro Diels±Alder Reactions in Stereoselective Synthesis Recent Res. Dev. Org. Chem. 1998 2 441±452 Keywords: retro-Diels±Alder reactions, stereoselective synthesis (9803) Almena I., Carrillo J. R., De la Cruz P., Diaz-Ortiz A., Gomez-Escalonilla M. J., De la Hoz A., Langa F., Prieto P., Sanchez-Migallon A. Application of Microwave Irradiation to Heterocyclic Chemistry Targets Heterocyclic Systems-Chemistry and Properties 1998 2 281±308, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. Keywords: Diels±Alder reactions, [60]-fullerene (9804) Rickborn B. The Retro-Diels±Alder Reaction. Part II. Dienophiles with One or More Heteroatoms Org. React. (N. 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Chem. 1998 196 45±89 Keywords: polycyclic aromatic hydrocarbons, photocyclization (9817) Johannsen M., Yao S., Graven A., Jorgensen K. A. Metal-Catalyzed Asymmetric Hetero-Diels±Alder Reactions of Unactivated Dienes With Glyoxylates Pure Appl. Chem. 1998 70 1117±1122 Keywords: stereoselectivity, metal complexes, glyoxylates (9818) Kobayashi S. New Types of Lewis Acids Used in Organic Synthesis Pure Appl. Chem. 1998 70 1019±1026 Keywords: aza-Diels±Alder reactions (9819) Ichihara A., Oikawa H. Diels±Alder Type Natural Products ± Structures and Biosynthesis Curr. Org. Chem. 1998 2 365±394 Keywords: biosynthesis, polyketides (9820) Kunz H., Hofmeister A., Glaser B. Stereoselective Syntheses Using Carbohydrates as Carriers of Chiral Information in ``Polysaccharides'' 1998 539, Ed. Severian D., Pb. Dekker N.Y. Keywords: stereoselective Diels±Alder cycloaddition (9821) Kumar A. Ionic Solutions and Their Pivotal Roles in Organic and Biological Systems Pure Appl. 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Tandem Reactions Combining Diels±Alder Reactions With Sigmatropic Rearrangement Processes and Their Use in Synthesis Synthesis 1998 227±255 (9828) Parker D. T. Hetero Diels±Alder Reactions in ``Org. Synth. Water.'' 1998 47, Ed. Grieco PA, Pb. Blackie, London Keywords: aqueous solvents (9829) Garner P. P. Diels±Alder Reactions in Aqueous Media in ``Org. Synth. Water.'' 1998 1, Ed. Grieco P. A., Pb. Blackie, London (9830) Vogt P. F., Miller M. J. Development and Applications of Amino Acid-Derived Chiral Acylnitroso Hetero Diels±Alder Reactions Tetrahedron 1998 54 1317±1348 Keywords: nitroso and acylnitroso dienophiles, hetero-Diels±Alder reaction (9831) Metz P. Sultones in Organic Synthesis J. Prakt. Chem. /Chem. ± Ztg. 1998 340 1±10 Keywords: intramolecular Diels±Alder reaction (9832) Tietze L. F., Kettschau G., Gewert J. A., Schuffenhauer A. Hetero-Diels±Alder Reactions of 1-Oxa-1,3-Butadienes Curr. Org. Chem. 1998 2 19±62 (9833) Langlois Y. New Uses of Oxazolines, Oxazoline N-Oxides and Dioxolanyliums in Asymmetric Synthesis Curr. Org. Chem. 1998 2 1±18 Keywords: Diels±Alder reaction, asymmetric synthesis (9834) Dell C. P. Cycloadditions in Synthesis J. Chem. Soc. Perkin Trans 1 1998 3873± 3905 Keywords: Lewis acids, asymmetric reactions, tandem, tethered, intramolecular reactions, o-quinodimethanes, o-quinone methides, hetero-Diels±Alder reactions (9835) Brandi A., Cicchi S. Domino Processes Involving Pericyclic reactions in Seminars in Organic Synthesis. 23th Summer Sch ``A. Corbella'' 1998 3, Ed. Trombini, Pb. Soc. Chim. Ital. Keywords: hetero-Diels±Alder reaction, nitrones, nitronates, carbonyl ylides (9836) Fringuelli F., Piermatti O., Pizzo F. Organic Synthesis in Unconventional Reaction Media Seminars in Organic Synthesis. 23th Summer Sch ``A. Corbella'' 1998 91, Ed. Di Furia F., Pb. Soc. Chim. Ital. Keywords: Diels±Alder reactions, water, Lewis acids (9837) Langlois Y. Chiral Auxiliaries for Asymmetric Cycloadditions Spec. Chem. 1998 18 405 Keywords: camphor derivatives, oxazoline-N-oxides (9838) Marrocchi A., Minuti L., Taticchi A. Diels±Alder reaction of Arylethenes in Organic Synthesis Recent Res. Dev. Org. Chem. 1998 2 107±129 Keywords: carbo-Diels±Alder reactions 1997 (9701) Ichihara A., Oikawa H. Biological Diels±Alder Reaction in Biosynthesis of Phytotoxins in ``Dyn. Aspects Nat. Prod. Chem.'' 1997 119, Eds. Ogoura K. and Sangawa U., Pb. Kodansha, Tokyo Keywords: biological Diels±Alder reaction in biosynthesis of phytotoxins, Diels±Alderase 310 Compilation (9702) Grimme W., Gossel J., Lex J. Diels±Alder Oligomers of Benzene NATO ASI Ser., Ser. C 1997 499 485±488 Keywords: cycloreversion, Diels±Alder oligomers, cycloreversion behavior (9703) Posner G. H., Bull D. S. Recent Advances in Control of Absolute Stereochemistry in Diels±Alder Cycloadditions of 2-Pyrones Recent Res. Dev. Org. Chem. 1997 1 259±271 Keywords: stereochemistry (9704) Gonzalez J., Sordo J. A. Theoretical Results on Hetero-Diels±Alder Reactions Recent Res. Dev. Org. Chem. 1997 1 239±257 Keywords: abinitio methods, FMO (molecular orbital), hetero-Diels±Alder reaction, transition state structure (9705) Pindur U., Lemster T. Recent Advances in the Synthesis of Carbazoles and Anellated Indoles With Antitumor Activity: DNA-Binding Ligands and Protein Kinase C Inhibitors Recent Res. Dev. Org. Bioorg. Chem. 1997 1 33±54 Keywords: Diels±Alder reactions of a 4,7-dioxo-indole with carbodienophiles (9706) Merour J. Y., Piroelle S., Joseph B. Synthesis and Reactivity of 1H-Indol-3(2H)One and Related Compounds Trends Heterocycl. Chem. 1997 5 115±126 Keywords: inverse electron-demand Diels±Alder reaction, indolone (9707) Klunder A. J. H., Zwanenburg B. Gas Phase Thermolysis in Natural Product Synthesis in ``Gas Phase React. Org. Synth.'' 1997 107, Ed. Yannick V., Pb. Gordon and Breach, Amsterdam Keywords: retro-Diels±Alder reaction, gas phase thermolysis in natural product synthesis (9708) Hanack M., Stihler P. Macrocyclic Metal Complexes As Ladder Polymers Macromol. Symp. 1998 131 49±58 Keywords: macrocyclic bis-dienes and dien-dienophiles (9709) Ishihara K., Yamamoto H. Asymmetric Synthesis With Chiral Lewis Acid Catalysts CATTECH 1997 1 51±62 Keywords: asymmetric synthesis, Lewis-acid catalysts (9710) Fringuelli F., Piermatti O., Pizzo F. Hetero Diels±Alder Reactions in Aqueous Medium Targets in Heterocyclic Systems-Chemistry and Properties 1997 1 57±73, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. Keywords: hetero-Diels±Alder reactions, retro-Diels±Alder reactions (9711) Cossu S., Fabris F., De Lucchi O. Synthetic Equivalents of Cyclohexatriene in [4 2] Cycloaddition Reactions. Methods for Preparing Cycloadducts to Benzene. Synlett 1997 1327±1334 Keywords: benzene, 1,3-cyclohexadienes (9712) Kappe C. O., Murphree S. S., Padwa A. Synthetic Applications of Furan Diels± Alder Chemistry Tetrahedron 1997 53 14179±14233 Keywords: intramolecular Diels±Alder reactions (9713) Mayer A., Meier H. 1,4-Epoxy Arenes for the Generation of Molecular Ribbons J. Prakt. Chem. /Chem. ± Ztg. 1997 339 679±681 Keywords: ladder polymers (9714) Sliwa W. Diels±Alder Reactions of Fullerenes Fullerene Sci. Technol. 1997 5 1133± 1175 Diels±Alder Reaction Compilation 311 (9715) Vallee Y., Chavant P. Y., Pinet S., Pelloux-Leon N., Arnaud R., Barone V. [4p 2p] Cycloadditions of N-Acyl-Thioformamides Phosphorus, Sulfur Silicon Relat. Elem. 1997 120 & 121 245±258 (9716) Dias L. C. Chiral Lewis Acid Catalysts in Diels±Alder Cycloadditions: Mechanistic Aspects and Synthetic Applications of Recent Systems J. Braz. Chem. Soc. 1997 8 289±332 Keywords: chiral Lewis-acid catalysts (9717) Tuulmets A. Ultrasound and Polar Homogeneous Reactions Ultrason. Sonochem. 1997 4 189±193 (9718) Ishihara K., Hattori K., Yamamoto H. Highly Stereoselective Synthesis of bAmino Esters via Double Stereodifferentiation in ``Enantiosel. Synth. b-Amino Acids'' 1997 159, Ed. Juaristi E., Pb. Wiley-VCH N.Y. Keywords: aza Diels±Alder reactions, b-amino esters (9719) Lee W. M., Chan W. H. Chiral Acetylenic Sulfoxides and Related Compounds in Organic Synthesis Top. Curr. Chem. 1997 190 103±129 Keywords: acetylenic sulfoxide, vinyl sulfoxide, acetylenic sulfinate, acetylenic sulfonate, 1-propene-1,3-sultone (9720) Cadogan J. I. G., Doyle A. A., Gosney I., Hodgson P. K. G., Thorburn P. Exerting Face-Stereoselective Shielding: Design of an Enantiomeric Pair of Camphene-Based Oxazolidin-2-Ones for Use As Recyclable Chiral Auxiliaries in Asymmetric Synthesis Enantiomer 1997 2 81±98 Keywords: ()-camphene (9721) Tietze L. F., Kettschau G. Hetero Diels±Alder Reactions in Organic Chemistry Top. Curr. Chem. 1997 189 1±120 (9722) Welker M. E., Wright M. W., Stokes H. L., Richardson B. M., Adams T. A., Smalley T. L., Vaughn S. P., Lohr G. J., Liable-Sands L., Rheingold A. L. Preparation and Exo-Selective [4 2] Cycloaddition Reactions of CobaloximeSubstituted 1,3-Dienes Adv. Cycloaddit. 1997 4 149±206 Keywords: exo(anti)selectivity (9723) Singleton D. A. Vinylboranes As Diels±Alder Dienophiles Adv. Cycloaddit. 1997 4 121±148 Keywords: regiochemistry, stereochemistry (9724) Corey E. J. Studies on Enantioselective Synthesis in ``Chiral Sep.'' 1997 37, Eds. Ahuja and Satinder, Pb. Am. Chem. Soc., Washington Keywords: enantioselective Diels±Alder reactions (9725) Wipf P., Xu W., Takahashi H., Jahn H., Coish P. D. G. Synthetic Applications of Organozirconocenes Pure Appl. Chem. 1997 69 639±644 Keywords: Diels±Alder reaction catalysts, organozirconocenes (9726) Fallis A. G. From Tartrate to Taxoids: a Double, Intramolecular Diels±Alder Strategy Pure Appl. Chem. 1997 6, 495±500 (9727) Radl S. 1,2,4-Triazoline-3,5-Diones Adv. Heterocycl. Chem. 1997 67 119±205 Keywords: Diels±Alder reactions (9728) Bunnage M. E. Nicolaou K. C. The Oxide Anion Accelerated Retro-Diels±Alder Reaction Chem. Eur. J. 1997 3 187±192 (9729) Liu Z. Y., Chu X. J., He L., Xie Y. N., Zhao L. Y. Natural Products Synthesis by Retro-Diels±Alder Reaction Youji Huaxue 1997 17 62±65 312 Compilation Keywords: pyrrolizidine alkaloids (9730) Schmittel M., Woehrle C., Bohn I. Radical Cation Initiated Cycloaddition of Electron-Rich Allenes. Evidence for a Stepwise Mechanism. Acta Chem. Scand. 1997 51 151±157 Keywords: radical cation, stepwise mechanism, electron-rich allenes (9731) Ichihara A., Oikawa H. Biosynthesis of Phytotoxins From Alternaria Solani Biosci., Biotechnol., Biochem. 1997 61 12±18 Keywords: biological Diels±Alder reaction, Diels±Alderase (9732) Dinjus E., Fornika R., Scholz M. Organic Chemistry in Supercritical Fluids in ``Chem. Extreme Non-Classical Cond.'' 1997 219, Eds. Van Eldick R. and Hubbard C., Pb. Wiley, N.Y. Keywords: Diels±Alder reactions (9733) Fukuzumi S. Catalysis on Electron Transfer and the Mechanistic Insight into Redox Reactions Bull. Chem. Soc. Jpn. 1997 70 1±28 Keywords: Mg2-catalyzed Diels±Alder reactions, anthracenes, p-benzoquinone, photoinduced electron transfer (9734) Ott M. A., Noordik J. H. Long-Range Strategies in the LHASA Program: The Quinone Diels±Alder Transform J. Chem. Inf. Comput. Sci. 1997 37 98±108 Keywords: computer application, quinone Diels±Alder transformations (9735) FruÈhauf H-W Metal-Assisted Cycloaddition reactions in Organotransition Metal Chemistry Chem. Rev. 1997 97 523±596 (9736) Harmata M. Intramolecular Cycloaddition Reactions of Allylic Cations Tetrahedron 1997 53 6235±6280 (9737) Hultin P. G., Earle M. A. and Sudharshan M. Synthetic Studies with Carbohydrate-Derived Chiral Auxiliaries Tetrahedron 1997 53 14823±14870 Keywords: sugar-linked dienes, sugar-linked dienophiles (9738) Aversa M. C., Barattucci A., Bonaccorsi P. and Giannetto P. Chiral Sulfinile-1,3dienes-Synthesis and Use in Asymmetric Reactions Tetrahedron:Asymmetry 1997 9 1339±1367 (9739) Ciobanu M. and Matsumoto K. Recent Advances in Organic Synthesis under High Pressure Liebigs Ann. der Chem. 1997 623±635 (9740) Minuti L. and Taticchi A. Multiple and High Pressure Diels±Alder Reactions in Seminars in Organic Synthesis 22th Summer Sch ``A. Corbella'' 1997 51, Ed. Trombini, Pb. Soc. Chim. Ital. Keywords: Lewis acids, stereoselectivity, multiple processes (9741) Desimoni G. and Faita G. Asymmetric Diels±Alder Reactions: A Rapid Growing Field in Organic Synthesis in Seminars in Organic Synthesis 22th Summer Sch ``A. Corbella'' 1997 71, Ed. Trombini, Pb. Soc. Chim. Ital. Keywords: acrylates, acrylamides, fumarates, a,b-unsaturated ketones, vinyl ethers, vinyl sulphoxides, chiral dienophiles, chiral dienes, chiral catalysts polymer-supported chiral Lewis acids (9742) Cozzi F. and Molteni V. Stereoselective Synthesis of Dihydropyrans by Hetero Diels±Alder Reactions in in Seminars in Organic Synthesis 22th Summer Sch ``A. Corbella'' 1997 95, Ed. Trombini, Pb. Soc. Chim. Ital. Keywords: carbonyl compounds, chiral dienophiles, chiral dienes, chiral catalysts, intramolecular cycloadditions, chiral Lewis acids Diels±Alder Reaction Compilation 313 (9743) Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords: natural products, metal catalyzed, asymmetric reactions, ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzoquinones, quinodimethanes, hetero-Diels±Alder reactions 1996 (9601) Kuber F. Metallocenes as a Source of Fine Chemicals. 2 in ``Appl. Homogeneous Catal. Organomet. Compd.'' 1996 2 893, Eds. Cornilis B. and Herrmann W. A., Pb. V. C. H., Weinheim Keywords: stereoselective Diels±Alder reaction catalysts, Diels±Alder chiral metallocene catalyst review (9602) Anwander R. Rare Earth Metals in Homogeneous Catalysis. 2 ``Appl. Homogeneous Catal. Organomet. Compd.'' 1996 2 866, Eds. Cornilis B. and Herrmann W. A., Pb. VCH, Weinheim Keywords: Diels±Alder reaction catalysts (9603) Engberts J. B. F. N., Feringa B. L., Keller E., Otto D. Lewis-Acid Catalysis of Carbon±Carbon Bond Forming Reactions in Water Recl. Trav. Chim. Pays-Bas 1996 115 457±464 Keywords: Lewis-acid catalyzed Diels±Alder reactions, reactions in water (9604) Langlois Y., Pouilhes A., Kouklovsky C., Morelli J. F., Haudrechy A., Kobayakawa M., Andre-Berres C., Berranger T., Dirat O. New Uses of Oxazolines, Oxazoline-N-Oxides and Dioxolanyliums in Asymmetric Synthesis Bull. Soc. Chim. Belg. 1996 105 639±657 Keywords: cationic Diels±Alder reaction, asymmetric synthesis, stereoselective Diels±Alder reaction (9605) Schildknegt K., Aube J. Ionic Diels±Alder Chemistry: Contemporary Interpretations of the Gassman Reaction Chemtracts: Org. Chem. 1996 9 237±241 Keywords: interpretations of Gassman reaction and ionic Diels±Alder chemistry (9606) Trost B. M. Molecular Gymnastics of Alkynes Orchestrated by Ruthenium Complexes Chem. Ber. 1996 129 1313±1322 Keywords: bis-homo-Diels±Alder reaction of 1,4-cyclooctadiene (9607) Boger D. L. Azadiene Diels±Alder Reactions: Scope and Applications. Total Synthesis of Natural and Ent-Fredericamycin A J. Heterocycl. Chem. 1996 33 1519±153. Keywords: inverse electron-demand Diels±Alder reactions, N-sulfonyl-1-aza1,3-butadiene (9608) Cativela C., Garcia J. I., Mayoral J. A., Salvatella L. Modeling of Solvent Effects on the Diels±Alder Reaction Chem. Soc. Rev. 1996 25 209±218 Keywords: solvent parameters, quantum chemical calculations, solvent effect (9609) Jenkins P. R. New Synthetic Methods in the Synthesis of Taxoids J. Braz. Chem. Soc. 1996 7 343±351 Keywords: terpenes, terpenoids, taxanes (9610) Walter C. J., Mackay L. G., Sanders JKM Can Enzyme Mimics Compete With Catalytic Antibodies? NATO ASI Ser., Ser. E 1996 320 419±428 Keywords: Diels±Alder reaction enzyme mimic 314 Compilation (9611) Thilgen C., Cardullo F., Haldimann R., Isaacs L., Seiler P., Diederich F., Boudon C., Gisselbrecht J. P., Gross M. Synthesis of Multiple Adducts of C60 With Specific Addition Patterns by Simple and Reversible (Templated) Tether-Directed Remote Functionalization Proc. ± Electrochem. Soc. 1996 96±10 1260±1271 Keywords: fullerene C60, regiochemistry (9612) Nie B., Rotello V. Reversible Covalent Attachment of Fullerenes to Polymers and Materials Proc. ± Electrochem. Soc. 1996 96±10 1212±1217 Keywords: Diels±Alder reaction of polymer supported cyclopentadiene with fullerene (9613) Whiting A. Asymmetric Diels±Alder Reactions in ``Adv. Asymmetric Synth.'' 1996 126, Ed. Stephenson G. R., Pb. Chapman and Hall, London Keywords: applications and future developments (9614) Averdung J., Torres-Garcia G., Luftmann H., Schlachter I., Mattay J. Progress in Fullerene Chemistry: From Exohedral Functionalization to Heterofullerenes. Fullerene Sci. Technol. 1996 4 633±654 Keywords: Diels±Alder reaction of exohedral functionalization of fullerenes and preparation of heterocyclic fullerenes (9615) Yli-Kauhaluoma J. Control of Regioselectivity, Diastereoselectivity and Enantioselectivity in the Antibody-Catalyzed Diels±Alder Reaction VTT Symp. 1996 163 69±74 Keywords: antibody catalysts for Diels±Alder reactions between 4-carboxybenzyl, trans-1,3-butadiene-1-carbamate and N,N-dimethylacrylamide (9616) Enders D., Meyer O. Diastereo- and Enantioselective Diels±Alder Reaction of 2Amino-1,3-Dienes Liebigs Ann. 1996 1023±1035 (9617) Clifford T., Bartle K. Chemical Reactions in Supercritical Fluids Chem. Ind. (London) 1996 449±452 Keywords: Diels±Alder reactions (9618) Ruano J. L. G., Carretero J. C., Carreno M. C., Cabrejas L. M. M., Urbano A. The Sulfinyl Group As a Chiral Inductor in Asymmetric Diels±Alder Reactions Pure Appl. Chem. 1996 68 925±930 (9619) Gilchrist T. L., Rocha Gonsalves A. M., Melo TMVD The Use of 2-Azadienes in the Diels±Alder Reaction Pure Appl. Chem. 1996 6, 859±862 Keywords: enamines, enones (9620) Mikami K. Asymmetric Catalysis of Carbonyl-Ene Reactions and Related CarbonCarbon Bond Forming Reactions Pure Appl. Chem. 1996 68 639±644 Keywords: hetero-Diels±Alder reactions, asymmetric catalysis (9621) Wong HNC Regiospecific Synthesis of Polysubstituted Furans and Their Application in Organic Synthesis Pure Appl. Chem. 1996 68 335±344 Keywords: 3,4-bis(trimethylsilyl)furan (9622) Streith J., Defoin A. Aza Sugar Syntheses and Multi-Step Cascade Rearrangements Via Hetero Diels±Alder Cycloadditions With Nitroso Dienophiles Synlett 1996 189±200 Keywords: stereochemistry, nitroso dienophiles (9623) Clasby M. C., Craig D., Jaxa-Chamiec A. 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Chem. 1993 165 1±69 Keywords: macropolycyclic structures (9306) Hassner A., Fischer B. New Chemistry of Oxazoles Heterocycles 1993 35 1441±1465 Keywords: Diels±Alder reactions of oxazoles with olefins or acetylenes, heterodienophiles (9307) Narasaka K., Iwasawa N. Asymmetric Reactions Promoted by Titanium Reagents Org. Synth.: Theory Appl. 1993 2 93±112 Keywords: asymmetric Diels±Alder reactions, chiral titanium reagent (9308) Price W. A., Silva A. M. S., Cavaleiro JAS 2-Styrylchromones: Biological Action, Synthesis and Reactivity Heterocycles 1993 36 2601±2611 Keywords: reactivity in Diels±Alder reaction (9309) Liu H. J., Chew S. Y., Yeh W. L. Facile Selective Diels±Alder Reactions of Chiral 5,5-Dimethyl-4,6-Methano-2-Methoxycarbonyl-2-Cyclohexenone. Application to the Total Synthesis of Qinghaosu. Youji Huaxue 1993 13 314±321 Keywords: ( )-b-pinene, asymmetric synthesis (9310) Eksterowicz J. E., Houk K. N. Transition-State Modeling With Empirical Force Fields Chem. Rev. 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Chem. 1992 6 202±217 Keywords: allenic sulfoxide, a-sulfinylmaleate, a-sulfinylmaleimide, asymmetric synthesis, chiral unsaturated sulfoxides (9212) Kagan H. B., Riant O. Catalytic Asymmetric Diels±Alder Reactions Chem. Rev. 1992 92 1007±1019 Keywords: asymmetric synthesis (9213) Lubineau A., Auge J., Bienayme H., Lubin N., Queneau Y. Aqueous Cycloadditions Using Glycoorganic Substrates. Stereo- and Physicochemical Aspects ACS Symp. Ser. 1992 494 147±157 Keywords: water as solvent, carbohydrates, stereoselectivity (9214) Herczegh P., Zsely M., Szilagyi L., Bajza I., Kovacs A., Batta G., Bognar R. Inter- and Intramolecular Diels±Alder Reactions of Sugar Derivatives ACS Symp. Ser. 1992 494 112±130 Keywords: chiral thiopyrans, intramolecular Diels±Alder reaction, diastereoselectivity, carbohydrates (9215) Horton D., Koh D., Takagi Y., Usui T. Diels±Alder Cycloaddition to Unsaturated Sugars. Stereocontrol As a Function of Structure and Stereochemistry ACS Symp. 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Elem. 1991 59 415±418 324 Compilation Keywords: retro-Diels±Alder reaction under flash vacuum thermolysis conditions (9125) Narasaka K. Chiral Lewis Acids in Catalytic Asymmetric Reactions Synthesis 1991 1±11 Keywords: stereoselectivity (9126) Dolbier WR J. r. Cycloadditions of Fluoroallene and 1,1-Difluoroallene Acc.Chem. Res. 1991 24 63±69 Keywords: Diels±Alder, facial selectivity (9127) Waldmann H. LiClO4 in Ether ± an Unusual Solvent Angew. Chem. Int. Ed. Engl. 1991 30 1306±1308 Keywords: Diels±Alder reaction (9128) Frei H. Chemistry with Red and Near Infrared Light Chimia 1991 45 175±190 Keywords: singlet-oxygen, photochemistry, furans 1990 (9001) Marcelis A. T. M., van der Plas H. C. Diels±Alder Reactions of Diazines and Pyridines Trends Heterocycl. Chem. 1990 1 111±123 (9002) Maat L. Novel Thebainelike Morphinandienes and Their Diels±Alder Adducts NIDA Res. Monogr. 1990 96 35±49 (9003) Suckling C. J. Catalytic Antibodies ± Catalysts from Scratch in ``Oppor. Biotransform.'', [Pap. Conf.] 1990 36 Ed. Copping L. G., Pb. Elsevier London (9004) Dannenberg J. J. The Molecular Orbital Modeling of Free Radical and Diels± Alder Reactions Adv. Mol. Model. 1990 2 1±63 Keywords: semiempirical MO methods (MNDO and AM1) (9005) Golebiowski A., Jurczak J. Total Synthesis of Lincomycin and Related Chemistry in ``Recent Prog. Chem. Synth. Antibiot.'' 1990 365, Eds. Lukacs G. and Ohno M., Pb. Springer Berlin Keywords: furan compounds, hetero-Diels±Alder reactions (9006) Thomas G. J. Synthesis of Anthracyclines Related to Daunomycin in ``Recent Prog. Chem. Synth. Antibiot.'' 1990 467, Eds. Lukacs G. and Ohno M., Pb. Springer Berlin Keywords: Diels±Alder reactions (9007) Fringuelli F., Taticchi A., Wenkert E. Diels±Alder Reactions of Cycloalkenones in Organic Synthesis. A Review. Org. Prep. Proced. Int. 1990 22 131±165 (9008) Fringuelli F., Taticchi A. Dienes in the Diels±Alder Reaction, 1990, Pb. Wiley N.Y. (9009) Smith M. B. N-Dienyl Amides and Lactams. Preparation and Diels±Alder Reactivity Org. Prep. Proced. Int. 1990 22 315±397 (9010) Roush W. R. Stereochemical and Synthetic Studies of the Intramolecular Diels± Alder Reaction Adv. Cycloaddit. 1990 2 91±146 Keywords: trienes (9011) Takeshita H., Mori A., Tian G. R. Carbon±Carbon Double Bond Formation by Means of High-Pressure Cycloaddition-Retro-Diels±Alder Reaction Between 2,3Bis(Methoxycarbonyl)-7-Oxanorbornadiene and Dienes Yuki Gosei Kagaku Kyokaishi 1990 48 132±143 (9012) Jung M. E. Substituent and Solvent Effects in Intramolecular Diels±Alder Reactions Synlett 1990 186±190 Diels±Alder Reaction Compilation 325 Keywords: kinetics of Diels±Alder reaction (9013) Okamura W. H., Curtin M. L. Pericyclization of Vinylallenes in Organic Synthesis: on the Intramolecular Diels±Alder Reaction Synlett 1990 1±9 Keywords: vinylallenes (9014) Tietze L. F. Domino-Reactions: the Tandem-Knoevenagel-Hetero-Diels±Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47±69 (9015) Barluenga J., Joglar J., Gonzales F. J. and Fustero S. Electronically Neutral 2-Aza1,3-Dienes : Are They Useful Intermediates in Organic Synthesis? Synlett 1990 129± 138 Keywords: diazasemibullvalene, pyridines, azaphosphorines 7.2 KEYWORD INDEX (CHAPTER 7) Ab initio methods (see also theory, MO calculation, quantum chemical) Acetylenic sulfoxides (chiral) Acetylene dicarboxylate Acrolein Acrylamides Acrylate esters containing F or CF3 Acrylates Acylimines Acylnitroso (dienophiles, derivated) Aldehydes Aldimines Alkadienes Alkenes Alkenyl (phenyl) iodonium Alkynes Alkynyl (phenyl) iodonium Allenes Allylic cations Alternaria solani Amides Aminoesters Aminodienes Aminophosphinephosphinites Amphiphilic gels Anionic clays 9704 9719 9921 9904 9741 9408 9741 9503 9830, 9512 9901, 9418, 9206 9902 0007, 9923, 9122 0002 9221 9630, 9511 9221 9730, 9501, 9304, 9211, 9013 9736 9731 9009 9830, 9718, 9520, 9115 9616, 9321 9811 9921 9932 Anthracenes Anthracyclines Antibodies 9733 9824, 9006 9615, 9610, 9311, 9220, 9108, 9107, 9104, 9103, 9102, 9003 Anti-tumor compounds 9824, 9313 Aqueous medium (see also 9829, 9828, 9710, water) 9512, 9312 Aromatic compounds 0002, 9816 Asymmetry (see also 0021, 9924, 9910, catalysis, 9909, 9902, 9834, enantioselectivity) 9833, 9810, 9743, 9741, 9738, 9709, 9630, 9625, 9620, 9618, 9613, 9604, 9520, 9518, 9513, 9510, 9503, 9420, 9418, 9416, 9321, 9309, 9307, 9301, 9223, 9212, 9211, 9118, 9114 Aza Diels±Alder reaction 9818, 9814, 9718, 9520, 9503, 9218, 9115, 9001 Azadienes 0013, 0006, 9934, 9813, 9626, 9619, 9607, 9015 Azaphosphorines 9015 Azapyrilium ions (dienes) 9511 Azasugar 9622 Azo compounds 0002, 9934 Azodienophiles 9508 326 Base catalyzed Diels± Alder reactions Bassard diene Benzene(s) Benzocyclobutenes Benzofurandiones Benzoquinones Benzyne Biological Diels±Alder reaction Biomolecules Biopolymer(s) Biosynthesis Bis-dienes Bis-dienophiles Bis-homo-Diels±Alder reaction Bis-oxazoline (copper complexes) Bornanes Boronates Boron catalysts (chiral) Butadienes Camphor derivatives Cantharidin Carbazole(s) Carbo Diels±Alder reaction Carboalkoxy-2-pyrones Carbocyclic derivatives Carbohydrates Carbonyl compounds (see also aldehydes, cycloalkenones, ketones) Carbonyl ylides Cascade Catalysis (see also Lewis acids, metal-catalyzed, transition metal) Cationic clays Cationic Diels±Alder reaction Cationic radical(s) Keyword Index 9936 9115 9711, 9702 9405 9931 9743, 9733, 9630 9101 0022, 9731, 9701, 9627 0004 9918 9819, 9701, 9514, 9409, 9204 9318 9318 9606 0008, 9903 9413 0026 9319 9932, 9923, 9321 9837, 9720, 9205 9302 0006, 9705, 9411 0101, 9903, 9838 9513 9505 9820, 9737, 9218, 9217, 9216, 9215, 9214, 9213, 9106 0017, 9742, 9620, 9505 9835 9631, 9622 0029, 0023, 0019, 0017, 0016, 9932, 9910, 9909, 9908, 9905, 9901, 9811, 9515, 9320, 9212 9932 9604 9805 Chiral Lewis acids (see also asymmetry, enantioselectivity, lanthanide, transition metal) Chirality (transient) Clay(s) Clerodane diterpenoids Cobaloxime-substituted 1,3-dienes Combinatorial synthesis Computer applications Concave reagents Consecutive Cooperativity of chirality Cotton Cyclacenes Cycloalkadienes Cycloalkenones Cyclohexatriene Cyclophanes Cyclopropane amino acids (synthesis) Cyclopropenes Cycloreversion (see also retro Diels±Alder reaction) Cytochalasan Daunomycin Decalin(s) Diastereofacial selectivity (see also facial selectivity) Diastereoselectivity (see also diastereofacial, stereoselectivity) Diazasemibullvalene Diazines Diels±Alderase Dien-dienophiles Dienes 0012, 0008, 9927, 9924, 9910, 9903, 9902, 9741, 9716, 9709 9930 0005, 9932 0003 9722 9824, 9628 9734 9808 9631 9112 9204 9318 0002, 9711, 9410, 9401, 9315, 9122 9707, 9317, 9309, 9007 9711 9219 9505 9111 9702 9119 9006 0003 9413, 9410, 9314 9317, 9214 9015 9001 9918, 9731, 9701 9708 0030, 0025, 0010, 0007, 9911, 9817, 9742, 9741, 9738, 9737, 9722, 9712, 9630, 9616, 9511, 9410, 9406, 9316, 9315, 9314, 9216, 9121, 9118, 9008 Diels±Alder Reaction Compilation Dienophiles Difluoroallene Dioxoindoles Dioxolanyliums Discovery of Diels±Alder reaction Discovery of orbital symmetry conservation rule Diterpenes Domino Drimane sesquiterpenes Electron-transfer Enamines Enantioselectivity (see also asymmetry) Ene reactions Enones (see also cycloalkenones) Environment Enzymic reactions Epoxyarenes Epoxydecalin(s) Ethyl glyoxylate Exo±endo (see also diastereoselectivity) Extrusion (Diels±Alder) Facial selectivity (see also diastereofacial) Flavonoids Fluoroacyl esters Fluoroallene(s) FMO theory Force fields Formylphosphonic acid derivatives Fragmentation in mass spectrometry Fragrance materials Fullerene(s) Fumarates 0031, 9804, 9742, 9741. 9737, 9705, 9410, 9406, 9306, 9218, 9118 9126 9705 9833, 9604 327 Furan(s) 9911, 9712, 9621, 9318, 9128, 9121, 9106, 9005 Gas-phase Glycosyl imines Glyoxylates 9707, 9404 9218 9817 Hetero-Diels±Alder 0101, 0017, 0008, 9936, 9935, 9934, 9922, 9913, 9907, 9901, 9835, 9834, 9831, 9830, 9828, 9817, 9743, 9721, 9710, 9704, 9630, 9622, 9620, 9511, 9506, 9502, 9416, 9406, 9216, 9122, 9112, 9014, 9005 9222 9222 0003 0033, 0024, 9835, 9014 9116 9733 9619 0012, 9901, 9811, 9724, 9623, 9616, 9509, 9419, 9303 9502 0009, 9618 0001, 0016 9919, 9610, 9414, 9403, 9107 9713 9911 9922 9722, 9317, 9214 9203 9916, 9413, 9410, 9314, 9215, 9126 9919, 9409 9408 9126 9938, 9704 9310 9917 9404 9206 0001, 9803, 9714, 9624, 9614, 9612, 9611 9741, 9114 Heterobimetallic complexes Heterocyclic compounds Heterodienes (see also dienes) Heterodienophiles (see also dienophiles) Heterofullerenes (see also fullerene) Heterogeneous catalysts Heterohelicenes High pressure Historical background Homo-Diels±Alder reaction Homogeneous catalysis Hydrazines Hydrazones Hydrindan dienes Hydrophobicity Imines Iminium cations Inclusion reaction Indole(s) Indolone 9905, 9908 0011, 9931, 9507, 9504 9511, 9121 9306 9614 9801 9413 0018, 9907, 9823, 9740, 9739, 9417, 9122, 9121, 9120, 9011 9222 9509, 9303, 9209 0009, 9801, 9717 9518 9518 9315 9123 9934, 9902, 9917, 9418 9934 0001 9912, 9705 9706 328 Indium, indium trichloride Intramolecular Diels± Alder reactions Inverse electron-demand reactions Iodonium compounds Ionic Diels±Alder reaction Ionic liquids Ionic solvents Isoindolones Isoprenoids Isothiocyanates Isoxazoles Isoxazolidines Isoxazolines Kaolinite Ketones (see also carbonyl compounds, cycloalkenones) Kinetics Lactams Lactate(s) Lactones Ladder polymers Lanthanide(s) (see also rare earth compounds) Laser-induced Lewis-acids (see also chiral Lewis acids, transition metal(s), lanthanides) Lincomycin Lithium perchlorate Macrocyclic bis-dienes Macrocyclic structures Maleimides (bis) Keyword Index 0019, 0029 9933, 9926, 9911, 9834, 9831, 9825, 9742, 9736, 9726, 9712, 9623, 9508, 9415, 9402, 9313, 9304, 9214, 9013, 9012, 9010 9912, 9813, 9706, 9625, 9607, 9513, 9511, 9407 9221 9805, 9743 0027, 9915 9821 0011 9409 0002 9203 9203 9203 0005 9901, 9907, 9741 0102, 9012, 9821 9808 9707 9928 9713, 9113 9927, 9920, 9814 9806 0101, 9924, 9834, 9818, 9807, 9742, 9740, 9603, 9506, 9502, 9418, 9407, 9215, 9125, 9117, 9114 9005 9127 9708 9708, 9318, 9305, 9119, 9109 9105 Manzamine alkaloids Mechanism Metal-catalyzed Metallocenes Mg(II)-catalyzed Microwave irradiation MO calculation Montmorillonite Moraceous plants Morphinadienes Mulberry tree Multifunctional catalysis Multi-step Natural Diels±Alder adducts Natural products synthesis Nitriles Nitroalkenes Nitronates Nitrones Nitroso compounds Norbornadiene Norbornenes Norgestrel (±) Nothapodytine B Nucleosides Oligomerizations (Diels± Alder) Oligomers Oppolzer's camphor sultam (see also camphor derivatives) Organometallics Organosilicon Organosulfur Organozirconocenes Orthoquinodimethanes Oxabutadienes Oxanorbornadiene(s) Oxazinolactams Oxazinones Oxazoles 9825 9938, 9730, 9120 9817, 9808, 9743, 9735, 9708 9601 9733 9803, 9519 9916, 9004 0005 9514, 9409 9002 9810, 9409, 9204 9908, 9905 9622 9514, 9204 0033, 0032, 0025, 0024, 0014, 9926, 9819, 9743 9729, 9415, 9406, 9217, 9014 9934 9631 9835, 9631 9835 9934, 9830, 9622, 9406 9303, 9209 9806, 9410 9302 9813 9505, 9106 9305 9702 9205 9626 9517 9630 9725 9504 9831 9011 9512 9121 9306, 9203 Diels±Alder Reaction Compilation Oxazolidinones Oxazolines Oxazolones Oxide anion(s) Pentaammineosmium(II) Perfumes Pericyclic reactions Pericyclization Phenolic compounds Phenylsulfonylalkenones Phospholes Photochemistry Photocyclization Photoinduced electron transfer Phytotoxins Pinene[(±)b] Piperidines Polyacenes Polycyclic hydrocarbons Polycyclics Polyenes Polyimides Polymers (see also ladder polymers) Polymer-supported Lewis acid Porphyrins Pr hfc3 (±) Pressure (see also high pressure) Pyranoindolones Pyranonaphthoquinone antibiotics Pyranones Pyridazinones Pyridines Pyridones Pyridoxazine Pyrones Pyrroles Pyrrolizidine alkaloids 9720 9837, 9833, 9604, 9203 9935 9728 9809 9206 9906, 9815, 9627, 9521 9013 9409 9506 9402, 9121 0001, 9210, 9128 9816 0001, 9733 9701 9309 9218 9318 9816, 9516 9109 0010 9202, 9105 9922, 9405, 9219, 9113, 9105 9741 0022, 9414 9407 9120 9410 0004 9216 9207 9015, 9001 9401, 9208, 9121, 9101 9512 9937, 9828, 9713, 9703, 9625, 9513, 9401, 9322, 9208, 9121 0022, 9809, 9121 9729 329 Quantum chemical calculations (see also theory, MO calculation, ab initio methods) Quinghaosu Quinodimethanes Quinone methides Quinones Radical cation(s) Rare earth compounds (see also lanthanides) Reactivity Regiochemistry Retro Diels±Alder reaction (see also cycloreversion) Rubber silicone Diels± Alder reactions Ruthenium complexes Saccharomyces Salt effects Scratch Semiconductor surfaces Sequential Sesquiterpenoids Seven-membered rings Silicones Silicon-tethered Siloxanes Silsesquioxanes Silyl derivatives Singlet-oxygen Solid phase synthesis Solvent effect(s) Stepwise mechanism (see also mechanism) Stereoelectronic effects Steroids Stereoselectivity 9608 9309 9834, 9743 9834 9734 9730 9927, 9920, 9814, 9625, 9602 9907, 9317 9937, 9931, 9723, 9707, 9624, 9621, 9516, 9317, 9101 0011, 9930, 9822, 9806, 9804, 9802, 9729, 9728, 9710, 9707, 9404, 9124, 9011 9517 9606 9207 0102 9003 0002 9631 9116 9928 9517 9516 9517 0009 9316 9128 9925, 9628 0032, 9814, 9608, 9110, 9012 9730 0007 9407, 9315, 9302 0003, 9907, 9938, 9930, 9928, 9923, 9913, 9821, 9820, 9817, 9808, 9807, 9802, 9740, 9626, 330 Steric effects Structure-reactivity Styrylchromones Substituent effects Sugar(s) Sulfinyl derivatives Sulfolenes Sulfonyl derivatives Sulfoxides Sulfur compounds Supercritical fluids Tandem Tartrate Taxanes Taxoids Terpenes Tether controlled Thebaines Theory (see also mechanism, quantum, MO calculation) Thermal Thioaldehydes Thioformamides Thiophene(s) Thiopyrans Thiopyridones Thiopyrones Titanium compounds Transanular Diels±Alder reaction Transition metal(s) (see also Lewis-acids) Transition state Triazolinediones Trienes Ultrasounds Uncatalyzed reactions Unconventional solvents Unsaturated compounds Keyword Index 9604, 9601, 9516, 9506, 9413, 9319, 9216, 9213, 9125 0007 9507 9308 9608, 9012 9737, 9516, 9215, 9214 9738, 9618, 9510, 9301, 9211 9417 9707, 9506 9913, 9719, 9510, 9211 9614 9731, 9617 9834, 9827, 9743, 9631, 9629, 9014 9726 9726, 9609 9726, 9609, 9313 9609 9926, 9834, 9743, 9516 9002 0028, 9938, 9826, 9704 9417, 9215, 9205 9124 9715 9914 9214 9208 9208 9420, 9401, 9307 9743, 9109 0012, 9924, 9515, 9509, 9402, 9316 9704. 9521, 9310 9727 9010 9717, 9412 9114 9110 0002 Vacuum thermolysis conditions Vanadium catalyst Vinylallene(s) Vinylborane(s) Vinylether(s) Vinylpyridines Vinylpyrrole(s) Vinylsulphoxides(s) Vitamin D-3 9124 9112 9013 9723 9741 9207 9809 9741 9623, 9407 Water (see also aqueous medium) 0101, 0020, 0016, 0015, 9836, 9829, 9828, 9710, 9603, 9213, 9201, 9123 Yeast 9207 Zeolites 9812, 9210
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